Aminothiazolones as estrogen related receptor-alpha modulators

ABSTRACT

The present invention relates to compounds of Formula (I), 
     
       
         
         
             
             
         
       
     
     methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoid arthritis, infectious arthritis, childhood arthritis, psoriatic arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury/loss, cartilage degeneration, and those related to cartilage formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway disease, chronic obstructive pulmonary disease, diabetes, disorders of energy homeostasis, gout, pseudogout, lipid disorders, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget&#39;s disease, periodontal disease, polymyalgia rheumatica, Reiter&#39;s syndrome, repetitive stress injury, hyperglycemia, elevated blood glucose level, and insulin resistance.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/305,181, filed on Feb. 17, 2010, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to certain novel compounds, methods forpreparing compounds, compositions, intermediates and derivatives thereofand for treating conditions such as cancer, arthritis, inflammatoryairway disease, and metabolic disorders. More particularly, thecompounds of the present invention are Estrogen Related Receptor alpha(ERR-α) modulators useful for treating, ameliorating, or inhibiting theprogression of disease states, disorders, and conditions mediated byERR-α activity.

BACKGROUND OF THE INVENTION

Nuclear receptors are members of a superfamily of transcription factors.The members of this family share structural similarities and regulate adiverse set of biological effects (Olefsky, J. M. J. Biol. Chem. 2001,276(40), 36863-36864). Ligands activate or repress these transcriptionfactors that control genes involved in metabolism, differentiation andreproduction (Laudet, V. and H. Gronmeyer. The Nuclear ReceptorFactbooks. 2002, San Diego: Academic Press). Presently, the human genomeproject has identified about 48 members for this family and cognateligands have been identified for about 28 of them (Giguere, V. EndocrineRev. 1999, 20(5), 689-725). This protein family is composed of modularstructural domains that can be interchanged within the members of thefamily without loss of function. A typical nuclear receptor contains ahypervariable N-terminus, a conserved DNA binding domain (DBD), a hingeregion, and a conserved ligand-binding domain (LBD). The function of theDBD is targeting of the receptor to specific DNA sequences (NuclearHormone Receptor (NHR) response elements or NREs), and the function ofthe LBD is recognition of its cognate ligand. Within the sequence of thenuclear receptor there are regions involved in transcriptionalactivation. The Activation

Function 1 (AF-1) domain is situated at the N-terminus andconstitutively activates transcription (Rochette-Egly, C. et al. Cell1997, 90, 97-107; Rochette-Egly, C. et al. Mol. Endocrinol. 1992, 6,2197-2209), while the Activation Function 2 (AF-2) domain is embeddedwithin the LBD and its transcriptional activation is ligand dependent(Wurtz, J. M. et al. Nat. Struct. Biol. 1996, 3, 87-94). Nuclearreceptors can exist as monomers, homodimers or heterodimers and bind todirect or inverted nucleotide repeats (Laudet and Gronmeyer, 2002;Aranda, A. and A. Pascual. Physiol. Rev. 2001, 81(3), 1269-1304).

The members of this family exist either in an activated or repressedbasal biological state. The basic mechanism of gene activation involvesligand dependent exchange of co-regulatory proteins. These co-regulatoryproteins are referred to as co-activators or co-repressors (McKenna, L.J. et al. Endocrine Rev. 1999, 20, 321-344). A nuclear receptor in therepressed state is bound to its DNA response element and is associatedwith co-repressor proteins that recruit histone de-acetylases (HDACs)(Jones, P. L. and Y. B. Shi. Curr. Top. Microbiol. Immunol. 2003, 274,237-268). In the presence of an agonist there is an exchange ofco-repressors with co-activators that in turn recruit transcriptionfactors that assemble into an ATP dependent chromatin-remodelingcomplex. Histones are hyper-acetylated, causing the nucleosome tounfold, and repression is alleviated. The AF-2 domain acts as the liganddependent molecular switch for the exchange of co-regulatory proteins.In the presence of an agonist the AF-2 domain undergoes a conformationaltransition and presents a surface on the LBD for interaction withco-activator proteins. In the absence of an agonist or in the presenceof an antagonist the AF-2 domain presents a surface that promotesinteractions with co-repressor proteins. The interaction surfaces on theLBD for both co-activators, and co-repressors overlap and provide aconserved molecular mechanism for gene activation or repression that isshared by the members of this family of transcription factors (Xu, H. E.et al. Nature 2002, 415 (6873), 813-817).

Natural ligands that modulate the biological activity of nuclearreceptors have been identified for only approximately one half of knownnuclear receptors. Receptors for which no natural ligand has beenidentified are termed “orphan receptors.” The discovery of ligands orcompounds that interact with an orphan receptor will accelerate theunderstanding of the role of the nuclear receptors in physiology anddisease and facilitate the pursuit of new therapeutic approaches;Estrogen related receptors (ERRs) constitute a sub-class of thesereceptors where no ligand has been identified.

ERR-α (also known as ERR-1), an orphan receptor, is the first of thethree identified members of the estrogen receptor related subfamily oforphan nuclear receptors (ERR-α, β, γ). The ERR subfamily is closelyrelated to the estrogen receptors (ER-α and ER-β). ERR-α and ERR-β werefirst isolated by a low stringency hybridization screen (Giguere, V. etal. Nature 1988, 331, 91-94) followed later with the discovery of ERR-y(Hong, H. et al. J. Biol. Chem. 1999, 274, 22618-22626). The ERRs andERs share sequence similarity with the highest homology observed intheir DBDs, approximately 60%, and all interact with the classical DNAestrogen response element. Recent biochemical evidence suggested thatthe ERRs and ERs share target genes, including pS2, lactoferin,aromatase and osteopontin, and share co-regulator proteins (Giguere, V.Trends in Endocrinol. Metab. 2002, 13, 220-225; Vanacker, J. M. et al.EMBO J. 1999, 18, 4270-4279; Kraus, R. J. et al. J. Biol. Chem. 2002,272, 24286-24834; Hong et al., 1999; Zhang, Z. and C. T. Teng. J. Biol.Chem. 2000, 275, 20387-20846). Therefore, one of the main functions ofERR is to regulate the response of estrogen responsive genes. The effectof the steroid hormone estrogen is primarily mediated in the breast,bone and endometrium. Thus, the identification of compounds that willinteract with ERRs should provide a benefit for the treatment of bonerelated disease, breast cancer and reproduction.

ERR-α is shown to be present both in normal and breast cancer tissue(Ariazi, E. A. et al. Cancer Res. 2002, 62, 6510-6518). It has beenreported that the main function of ERR-α in normal breast tissue is thatof a repressor for estrogen responsive genes. In breast cancers or celllines that are non-estrogen responsive (ER-α negative), ERR-α has beenreported to be in an activated state (Ariazi et al., 2002). Therefore,compounds that will interact with ERR-α may be useful agents for thetreatment of breast cancer that is ER-a negative and non-responsive toclassical anti-estrogenic therapy, or may be used as an adjunct agentfor anti-estrogen responsive breast cancers. These agents may act asantagonists by reducing the biological activity of ERR-α in theseparticular tissues.

Many post-menopausal women experience osteoporosis, a condition that isa result of the reduction of estrogen production. Reduction of estrogenlevels results in an increase of bone loss (Turner, R. T. et al.Endocrine Rev. 1994, 15(3), 275-300). An anabolic effect on bonedevelopment has been observed on the administration of estrogens topostmenopausal patients with osteoporosis (Pacifici, R. J. Bone Miner.Res. 1996, 11(8), 1043-1051) but the molecular mechanism is unknownsince ER-α and ER-β knock-out animals have minor skeletal defects, wherethe action of estrogens is typically mediated (Korach, K. S. Science1994, 266, 1524-1527; Windahl, S. H. et al. J. Clin. Invest. 1999,104(7), 895-901). Expression of ERR-α in bone is regulated by estrogen(Bonnelye, E. et al. Mol. Endocrin. 1997, 11, 905-916; Bonnelye, E. etal. J. Cell Biol. 2001, 153, 971-984). ERR-α is maintained throughoutosteoblast differentiation stages. Over-expression of ERR-α in ratcalvaria osteoblasts, an accepted model of bone differentiation, resultsin an increase of bone nodule formation, while treatment of rat calvariaosteoblasts with ERR-α antisense results in a decrease of bone noduleformation. ERR-α also regulates osteopontin, a protein believed to beinvolved in bone matrix formation. Therefore compounds that willmodulate ERR-α by increasing its activity can have an anabolic effectfor the regeneration of bone density and provide a benefit over currentapproaches that prevent bone loss, but have no anabolic effect. Suchcompounds can enhance the activity of the receptor by two possiblemechanisms: i) enhancing the association of the receptor with proteinsthat enhance its activity or improve the stability of the receptor; andii) increasing the intracellular concentrations of the receptor andconsequently increasing its activity. Conversely, with respect to bonediseases that are a result of abnormal bone growth, compounds that willinteract with ERR-α and decrease its biological activity may provide abenefit for the treatment of these diseases by retarding bone growth.Antagonism of the association of the receptor with co-activator proteinsdecreases the activity of the receptor.

ERR-α is also present in cardiac, adipose, and muscle tissue and forms atranscriptional active complex with the PGC-1 co-activator family,co-activators implicated with energy homeostasis, mitochondriabiogenesis, hepatic gluconeogenesis and in the regulation of genesinvolved in fatty acid beta-oxidation (Kamei, Y. et al. Proc. Natl.Acad. Sci. USA 2003, 100(21), 12378-12383). ERR-α regulates theexpression of the medium chain acyl-CoA dehydrogenase promoter (MCAD).Medium chain acyl-CoA dehydrogenase is a gene involved in the initialreaction in fatty acid beta-oxidation. It is believed that in theadipose tissue ERR-α regulates energy expenditure through the regulationof MCAD (Sladek, R. et al. Mol. Cell. Biol. 1997, 17, 5400-5409; Vega,R. B. and D. P. Kelly. J. Biol. Chem. 1997, 272, 31693-31699). Inantisense experiments in rat calvaria osteoblasts, in addition to theinhibition of bone nodule formation, there was an increase in adipocytedifferentiation markers including aP2 and PPAR-γ (Bonnelye, E. et al.Endocrinology 2002, 143, 3658-3670). Recently an ERR-α knockout modelhas been described that exhibited reduced fat mass relative to the wildtype and DNA chip analysis data indicated alteration of the expressionlevels of genes involved in adipogenesis and energy metabolism (Luo, J.et al. Mol. Cell. Biol. 2003, 23(22), 7947-7956). More recently it hasbeen shown that ERR-α regulates the expression of endothelial nitricoxide synthase, a gene that has a protective mechanism againstarteriosclerosis (Sumi, D. and L. J. Ignarro. Proc Natl. Acad. Sci.2003, 100, 14451-14456). The biochemical evidence supports theinvolvement of ERR-α in metabolic homeostasis and differentiation ofcells into adipocytes. Therefore, compounds interacting with ERR-α canaffect energy homeostasis and may therefore provide a benefit for thetreatment of obesity and metabolic syndrome related disease indications,including arteriosclerosis and diabetes (Grundy, S. M. et al.Circulation 2004, 109(3), 433-438).

There is a continuing need for new ERR-α modulators. There is also aneed for ERR-α modulators useful for the treatment of conditionsincluding but not limited to ankylosing spondylitis, artherosclerosis,arthritis (such as rheumatoid arthritis, infectious arthritis, childhoodarthritis, psoriatic arthritis, reactive arthritis), bone-relateddiseases (including those related to bone formation), breast cancer(including those unresponsive to anti-estrogen therapy), cardiovasculardisorders, cartilage-related disease (such as cartilage injury/loss,cartilage degeneration, and those related to cartilage formation),chondrodysplasia, chondrosarcoma, chronic back injury, chronicbronchitis, chronic inflammatory airway disease, chronic obstructivepulmonary disease, diabetes, disorders of energy homeostasis, gout,pseudogout, lipid disorders, metabolic syndrome, multiple myeloma,obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bonemetastasis, osteomalacia, osteoporosis, Paget's disease, periodontaldisease, polymyalgia rheumatica, Reiter's syndrome, repetitive stressinjury, hyperglycemia, elevated blood glucose level, and insulinresistance.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides novel compoundsuseful as, for example, ERR-α modulators, methods of preparing suchcompounds, pharmaceutical compositions comprising one or more suchcompounds, methods of preparing pharmaceutical compositions comprisingone or more such compounds, and methods of treatment, amelioration, orinhibition of one or more diseases associated with ERR-α using suchcompounds or pharmaceutical compositions.

One aspect of the present invention features a compound of Formula (I)

wherein

X is CH or N;

R₁ is C₁₋₄alkyl, halo, or —C(O)—C₁₋₄alkyl; wherein the C₁₋₄alkyl may besubstituted with halo;

R₂ is halo, cyano, H, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkoxy,—C(O)N(R⁵)(R⁶), or hydroxyl; wherein the C₁₋₄alkyl may be substitutedwith halo;

R₃ is H, halo, —CN, or C₁₋₄alkyl; and

R₄ is heteroaryl, C₁₋₄alkyl, cycloalkyl, or heterocyclyl;

wherein said C₁₋₄alkyl may be substituted with one to five groups, saidgroups independently selected from halo, —OR⁵, cycloalkyl, —N(R⁵)(R⁶),—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —SO₂N(R⁵)(R⁶), —O—C₁₋₄alkyl—OR⁵, heterocyclyloptionally substituted with halo, oxo or C₁₋₄alkyl, and heteroaryloptionally substituted with C₁₋₄alkyl;

wherein said cycloalkyl may be substituted with one to three groups,said groups independently selected from halo, —C(O)OR⁵, and C₁₋₄alkyl;

wherein said heterocyclyl may be independently substituted with one tothree groups, said groups independently selected from halo, C₁₋₄alkyl,and —OR⁵; wherein said C₁₋₄alkyl may be substituted with —OR⁵;

wherein R⁵ and R⁶ are independently H or C₁₋₄ alkyl;

or an optical isomer, enantiomer, diastereomer, cis-trans isomer,racemate, or pharmaceutically acceptable salt thereof.

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionmediated by

ERR-a activity, comprising administering to the subject atherapeutically effective amount of at least one compound of Formula(I). Such disease, disorder, or condition can include, but is notlimited to ankylosing spondylitis, artherosclerosis, arthritis (such asrheumatoid arthritis, infectious arthritis, childhood arthritis,psoriatic arthritis, reactive arthritis), bone-related diseases(including those related to bone formation), breast cancer (includingthose unresponsive to anti-estrogen therapy), cardiovascular disorders,cartilage-related disease (such as cartilage injury/loss, cartilagedegeneration, and those related to cartilage formation),chondrodysplasia, chondrosarcoma, chronic back injury, chronicbronchitis, chronic inflammatory airway disease, chronic obstructivepulmonary disease, diabetes, disorders of energy homeostasis, gout,pseudogout, lipid disorders, metabolic syndrome, multiple myeloma,obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bonemetastasis, osteomalacia, osteoporosis, Paget's disease, periodontaldisease, polymyalgia rheumatica, Reiter's syndrome, repetitive stressinjury, hyperglycemia, elevated blood glucose level, and insulinresistance. The therapeutically effective amount of the compound ofFormula (I) can be from about 0.1 mg/day to about 5000 mg/day.

The present invention further features a process for making apharmaceutical composition comprising admixing any of the compoundsaccording to Formula (I) and a pharmaceutically acceptable carrier.

Additional embodiments and advantages of the invention will becomeapparent from the detailed discussion, schemes, examples, and claimsbelow.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel ERR-α modulators and compositionsthereof for the treatment, amelioration, or inhibition of numerousconditions, including but not limited to cancer, arthritis, inflammatoryairway disease, bone-related diseases, metabolic disorders, andassociated symptoms or complications thereof.

One aspect of the present invention features a compound of Formula (I)

wherein

X is CH or N;

R₁ is C₁₋₄alkyl, halo, or —C(O)—C₁₋₄alkyl; wherein the C₁₋₄alkyl may besubstituted with halo;

R₂ is halo, cyano, H, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkoxy,—C(O)N(R⁵)(R⁶), or hydroxyl; wherein the C₁₋₄alkyl may be substitutedwith halo;

R₃ is H, halo, —CN, or C₁₋₄alkyl; and

R₄ is heteroaryl, C₁₋₄alkyl, cycloalkyl, or heterocyclyl;

wherein said C₁₋₄alkyl may be substituted with one to five groups, saidgroups independently selected from halo, —OR⁵, cycloalkyl, —N(R⁵)(R⁶),—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —SO₂N(R⁵)(R⁶), —o—C₁₋₄alkyl—OR⁵, heterocyclyloptionally substituted with halo, oxo or C₁₋₄alkyl, and heteroaryloptionally substituted with C₁₋₄alkyl;

wherein said cycloalkyl may be substituted with one to three groups,said groups independently selected from halo, —C(O)OR⁵, and C₁₋₄alkyl;

wherein said heterocyclyl may be independently substituted with one tothree groups, said groups independently selected from halo, C₁₋₄alkyl,and —OR⁵; wherein said C₁₋₄alkyl may be substituted with —OR⁵;

wherein R⁵ and R⁶ are independently H or C₁₋₄ alkyl;

or an optical isomer, enantiomer, diastereomer, cis-trans isomer,racemate, or pharmaceutically acceptable salt thereof.

In particular, the present invention includes a cis-trans isomer of thecompound of Formula (I), which has the following structure, wherein X,R₁, R₂, R₃ and R₄ are as described above:

Particularly, X is CH.

Particularly, R₁ is —C(O)—C₁₋₂alkyl, —CL, —Br, —I or C₁₋₃alkyl; whereinsaid C₁₋₃alkyl may be substituted with halo. More particularly, R₁ is—C(O)—CH₃, —Cl, —Br, —I, or —CF₃.

Particularly, R₂ is CF₃, —F, —Cl, —Br, C₁₋₂alkoxy or hydroxyl.

Particularly, R₃ is H or halo.

Particularly, R₄ is selected from:

One aspect of the present invention features a compound of Formula (I)wherein

X is CH;

R₁ is —C(O)—C₁₋₂alkyl, —Cl, —Br, —I, or C₁₋₃alkyl; wherein saidC₁₋₃alkyl may be substituted with halo;

R₂ is —CF₃, —F, —Cl, —Br, C₁₋₂alkoxy or hydroxyl;

R₃ is H or halo; and

R₄ is selected from:

Particularly, the present invention includes a compound of Formula (I)wherein

X is CH;

R₁ is —CF₃,—Cl, —Br, or —I;

R₂ is CF₃, —OCH₃, —F or —Cl;

R₃ is H or halo; and

R₄ is selected from:

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH;

R₁ is CF₃;

R₂ is CF₃, —OCH₃, or —Cl;

R₃ is H; and

R₄ is selected from:

Preferred embodiments of the present invention include compounds ofFormula (I) wherein R₄ is selected from:

One aspect of the present invention features a compound of Formula (I)wherein

X is CH;

R₁ is —C(O)—C₁₋₂alkyl, —Cl, —Br, —I, or C₁₋₃alkyl; wherein saidC₁₋₃alkyl may be substituted with halo;

R₂ is —CF₃, —F, —Cl, —Br, C₁₋₂alkoxy or hydroxyl;

R₃ is H or halo; and

R₄ is selected from:

Particularly, the present invention includes a compound of Formula (I)wherein

X is CH;

R₁ is —CF₃,—Cl, —Br, or —I;

R₂ is —CF₃, —OCH₃, —F or —Cl;

R₃ is H or halo; and

R₄ is selected from:

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH;

R₁ is —CF₃;

R₂ is —CF₃, —OCH₃, or —Cl;

R₃ is H; and

R₄ is selected from:

It is an embodiment of the present invention to provide a compoundselected from:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid;-   4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one;-   5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-2-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-1,3-thiazol-4(5H)-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1-methyl-piperidin-4-ylamino)-thiazol-4-one;-   2-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyric    acid;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one;-   (S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-45-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid; and-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric    acid.

Particularly, the present invention provides a compound selected from:

-   4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyric    acid;-   (S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid; and-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric    acid.

More particularly, the present invention provides a compound selectedfrom:

-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyric    acid;-   (S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid; and-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric    acid.

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier. Particularly, a pharmaceuticalcomposition of the present invention can further comprise at least oneadditional agent, drug, medicament, antibody and/or inhibitor fortreating, ameliorating or inhibiting the progression of an ERR-αmediated disease. A pharmaceutical composition of the present inventioncomprises a compound selected from:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid;-   4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one;-   5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-2-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-1,3-thiazol-4(5H)-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1-methyl-piperidin-4-ylamino)-thiazol-4-one;-   2-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyric    acid;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one;-   (S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid; and-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric    acid.

Particularly, a pharmaceutical composition of the present inventioncomprises at least a compound selected from:

-   4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyric    acid;-   (S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid; and-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric    acid.

More particularly, a pharmaceutical composition of the present inventioncomprises at least a compound selected from:

-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyric    acid;-   (S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic    acid; and-   4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric    acid.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionmediated by ERR-a activity, comprising administering to the subject atherapeutically effective amount of at least one compound of Formula(I).

The present invention also features a method for inhibiting theprogression of an ERR-α-mediated condition in a subject in need thereof,comprising administering to said subject a therapeutically effectiveamount of at least one compound of Formula (I).

The present invention also features a method for treating a prediabeticcondition in a subject in need thereof, comprising administering to saidsubject a therapeutically effective amount of at least one compound ofFormula (I).

Such disease, disorder, or condition can include, but is not limited toankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoidarthritis, infectious arthritis, childhood arthritis, psoriaticarthritis, reactive arthritis), bone-related diseases (including thoserelated to bone formation), breast cancer (including those unresponsiveto anti-estrogen therapy), cardiovascular disorders, cartilage-relateddisease (such as cartilage injury/loss, cartilage degeneration, andthose related to cartilage formation), chondrodysplasia, chondrosarcoma,chronic back injury, chronic bronchitis, chronic inflammatory airwaydisease, chronic obstructive pulmonary disease, diabetes, disorders ofenergy homeostasis, gout, pseudogout, lipid disorders, metabolicsyndrome, multiple myeloma, obesity, osteoarthritis, osteogenesisimperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis,Paget's disease, periodontal disease, polymyalgia rheumatica, Reiter'ssyndrome, repetitive stress injury, hyperglycemia, elevated bloodglucose level, and insulin resistance.

According to one aspect of the invention, the disclosed compounds andcompositions are useful for the amelioration of symptoms associatedwith, the treatment of, and inhibiting the progression of, the followingconditions and diseases: bone-related disease, bone formation, cartilageformation, cartilage loss, cartilage degeneration, cartilage injury,ankylosing spondylitis, chronic back injury, gout, osteoporosis,osteolytic bone metastasis, multiple myeloma, chondrosarcoma,chondrodysplasia, osteogenesis imperfecta, osteomalacia, Paget'sdisease, polymyalgia rheumatica, pseudogout, arthritis, rheumatoidarthritis, infectious arthritis, osteoarthritis, psoriatic arthritis,reactive arthritis, childhood arthritis, Reiter's syndrome, andrepetitive stress injury.

According to another aspect of the invention, the disclosed compoundsand compositions are useful for the amelioration of symptoms associatedwith, the treatment of, and inhibiting the progression of, the followingconditions and diseases: periodontal disease, chronic inflammatoryairway disease, chronic bronchitis, and chronic obstructive pulmonarydisease.

According to a further aspect of the invention, the disclosed compoundsand compositions are useful for the amelioration of symptoms associatedwith, the treatment of, and inhibiting the progression of breast cancer.

According to yet another aspect of the invention, the disclosedcompounds and compositions are useful for the amelioration of symptomsassociated with, the treatment of, and inhibiting the progression of,the following conditions and diseases: metabolic syndrome, obesity,disorders of energy homeostasis, diabetes, lipid disorders,cardiovascular disorders, artherosclerosis, hyperglycemia, elevatedblood glucose level, and insulin resistance.

Particularly, a method of the present invention comprises administeringto the subject a therapeutically effective amount of (a) at least onecompound of Formula (I); and (b) at least one additional agent selectedfrom an anti-diabetic agent, an anti-obesity agent, a lipid loweringagent, an anti-thrombotic agent, direct thrombin inhibitor, and a bloodpressure lowering agent, said administration being in any order. Moreparticularly, the additional agent in (b) is an anti-obesity agentselected from CB1 antagonists, monoamine reuptake inhibitors, MTPinhibitors and lipase inhibitors. More particularly, the additionalagent in (b) is an anti-diabetic agent selected from metformin, DPP-IVinhibitors, GLP-1 mimetics, glucokinase modulators, glucagonantagonists, SGLT2 inhibitors, PPARγ agonists and GPR119 modulators.More particularly, the additional agent in (b) is selected fromMetformin, Sitagliptin and Pioglitazone.

The present invention also features a method for treating or inhibitingthe progression of one or more ERR-α-mediated conditions, said methodcomprising administering to a patient in need of treatment apharmaceutically effective amount of a composition of the invention.

It is a further embodiment of the invention to provide a process formaking a pharmaceutical composition comprising admixing any of thecompounds according to Formula (I) and a pharmaceutically acceptablecarrier.

The invention also features pharmaceutical compositions which include,without limitation, one or more of the disclosed compounds, andpharmaceutically acceptable carriers or excipients.

In a further embodiment of the invention, a method for treating orameliorating an ERR-α-mediated condition in a subject in need thereofcomprises administering to the subject a therapeutically effectiveamount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5000 mg/dose. In particular, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.5 mg/dose to about 1000 mg/dose. More particularly, thetherapeutically effective amount of the compound of Formula (I) is fromabout 1 mg/dose to about 100 mg/dose. In a further embodiment of theinvention, the number of doses per day of a compound of Formula (I) isfrom 1 to 3 doses. In a further embodiment of the invention, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.001 mg/kg/day to about 30 mg/kg/day. More particularly, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.01 mg/kg/day to about 2 mg/kg/day.

In a further embodiment of the invention, a method for inhibiting theprogression of an ERR-α-mediated condition in a subject in need thereofcomprises administering to the subject a therapeutically effectiveamount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5000 mg/dose. In particular, thetherapeutically effective amount of the compound of Formula (I) is fromabout 1 mg/dose to about 100 mg/dose. In a further embodiment of theinvention, the number of doses per day of a compound of Formula (I) isfrom 1 to 3 doses. In a further embodiment of the invention, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.001 mg/kg/day to about 30 mg/kg/day. More particularly, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.01 mg/kg/day to about 2 mg/kg/day.

In yet another embodiment of the invention, a method for treating aprediabetic condition in a subject in need thereof, comprisesadministering to said subject a therapeutically effective amount of atleast one compound of Formula (I), wherein the therapeutically effectiveamount of the compound of Formula (I) is from about 0.1 mg/dose to about5000 mg/dose. In particular, the therapeutically effective amount of thecompound of Formula (I) is from about 1 mg/dose to about 100 mg/dose. Ina further embodiment of the invention, the number of doses per day of acompound of Formula (I) is from 1 to 3 doses. In a further embodiment ofthe invention, the therapeutically effective amount of the compound ofFormula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/day. Moreparticularly, the therapeutically effective amount of the compound ofFormula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day.

The invention is further described below.

A) Terms

Some terms are defined below and by their usage throughout thisdisclosure.

Unless otherwise noted, “alkyl” as used herein, whether used alone or aspart of a substituent group, refers to a saturated, branched, orstraight-chain monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane. Typicalalkyl groups include, but are not limited to, methyl; ethyls such asethanyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl;butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,2-methyl-propan-2-yl, cyclobutan-1-yl and the like. In preferredembodiments, the alkyl groups are C₁₋₆alkyl, with C₁₋₃ beingparticularly preferred. “Alkoxy” radicals are oxygen ethers formed fromthe previously described straight or branched chain alkyl groups.

As used herein, “halo” or “halogen” shall mean chlorine, bromine,fluorine and iodine. “Halo substituted” shall mean a group substitutedwith at least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include, but are not limited to —CF₃,—CH₂—CHF₂, —CH₂—CF₃, and the like.

The term “cycloalkyl,” as used herein, refers to a stable, saturated orpartially saturated monocyclic or bicyclic ring system containing from 3to 8 ring carbons and preferably 5 to 7 ring carbons. Examples of suchcyclic alkyl rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

The term “alkenyl” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical, which has at least onecarbon-carbon double bond, derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The radical may be ineither the cis or trans conformation about the double bond(s). Typicalalkenyl groups include, but are not limited to, ethenyl; propenyls suchas prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like.

The term “alkynyl” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical, which has at least onecarbon-carbon triple bond, derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “heteroaryl” refers to a monovalent heteroaromatic radicalderived by the removal of one hydrogen atom from a single atom of aparent heteroaromatic ring system. Typical heteroaryl groups includemonocyclic and bicyclic systems where one or both rings areheteroaromatic. Heteroaromatic rings may contain 1-4 heteroatomsselected from O, N, and S. Examples include but are not limited to,radicals derived from carbazole, imidazole, indazole, indole,indolizine, isoindole, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, purine, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

The term “aryl,” as used herein, refers to aromatic groups comprising astable six-membered monocyclic, or ten-membered bicyclic orfourteen-membered tricyclic aromatic ring system which consists ofcarbon atoms. Examples of aryl groups include, but are not limited to,phenyl or naphthalenyl.

The term “heterocyclyl” or “heterocycle” is a 3- to 12-member saturated,or partially saturated single or fused ring system which consists ofcarbon atoms and from 1 to 6 heteroatoms selected from N, O and S. Theheterocyclyl group may be attached at any heteroatom or carbon atomwhich results in the creation of a stable structure. Example ofheterocyclyl groups include, but are not limited to, 2-imidazoline,imidazolidine; azetidine, morpholine, oxazoline, 2-pyrroline,3-pyrroline, pyrrolidine, pyridone, pyrimidone, piperazine, piperidine,indoline, tetrahydrofuran, 2-pyrroline, 3-pyrroline, 2-imidazoline,2-pyrazoline, indolinone, tetrahydroquinoline, tetrahydroquinazoline,and the like.

The term “oxo” whether used alone or as part of a substituent grouprefers to an O═ to either a carbon or a sulfur atom. For example,phthalimide and saccharin are examples of compounds with oxosubstituents.

The term “cis-trans isomer” refers to stereoisomeric olefins orcycloalkanes (or hetero-analogues) which differ in the positions ofatoms (or groups) relative to a reference plane: in the cis-isomer theatoms are on the same side; in the trans-isomer they are on oppositesides.

The term “substituted” refers to a radical in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). A substituted group comprising alkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is the object of treatment,observation or experiment.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Metabolic disorders, diseases, or conditions include, but are notlimited to, diabetes, obesity, and associated symptoms or complicationsthereof. They include such conditions as IDDM (insulin-dependentdiabetes mellitus), NIDDM (non insulin-dependent diabetes mellitus), IGT(Impaired Glucose Tolerance), IFG (Impaired Fasting Glucose), Syndrome X(or Metabolic Syndrome), hyperglycemia, elevated blood glucose level,and insulin resistance. A condition such as IGT or IFG is also known asa “prediabetic condition” or “prediabetic state.”

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“therapeutically effective amount” as used herein, means that amount ofeach active compound or pharmaceutical agent, alone or in combination,that elicits the biological or medicinal response in a tissue system,animal or human that is being sought by a researcher, veterinarian,medical doctor or other clinician, which includes alleviation of thesymptoms of the disease or disorder being treated. For prophylacticpurposes (i.e., inhibiting the progression of a disorder), the term“therapeutically effective amount” refers to that amount of each activecompound or pharmaceutical agent, alone or in combination, that treatsor inhibits in a subject the progression of a disorder as being soughtby a researcher, veterinarian, medical doctor or other clinician. Thus,the present invention provides combinations of two or more drugswherein, for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both (ormore) drugs are administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

The term “pharmaceutically acceptable salt” refers to non-toxicpharmaceutically acceptable salts (Ref. International J. Pharm., 1986,33, 201-217; J. Pharm. Sci., 1997 (Jan), 66, 1, 1). Other salts wellknown to those in the art may, however, be useful in the preparation ofcompounds according to this invention or of their pharmaceuticallyacceptable salts. Representative organic or inorganic acids include, butare not limited to, hydrochloric, hydrobromic, hydriodic, perchloric,sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

B) Compounds

Representative compounds of the present invention are listed in Table Ibelow:

TABLE I COM- STRUCTURE POUND # NAME

1 2-(3-Dimethylamino- propylamino)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

2 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(3- dimethylamino-propylamino)- thiazol-4-one

3 5-[1-(4-Chloro-2-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(3-dimethylamino- propylamino)-thiazol-4-one

4 {5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}- aceticacid

5 5-[1-(4-Methoxy-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2- morpholin-4-yl-ethylamino)- thiazol-4-one

6 5-[1-(4-Methoxy-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2- pyrrolidin-1-yl-ethylamino)- thiazol-4-one

7 5-[1-(4-Methoxy-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2- oxo-pyrrolidin-1-yl)-propylamino]-thiazol-4-one

8 5-[1-(2,4-Dichloro-benzyl)-1H- indazol-5-ylmethylene]-2-[2-(2-hydroxy-ethoxy)-ethylamino]- thiazol-4-one

9 2-(2S,3-Dihydroxy- propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

10 2-(2R,3-Dihydroxy- propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

11 2-(2,2-Difluoro-ethylamino)-5- [1-(4-methoxy-2-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

12 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(2-morpholin- 4-yl-ethylamino)-thiazol-4-one

13 1-{5-[1-(4-Methoxy-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic acid

14 1-{5-[1-(2,4-Bis- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic acid

15 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-[(2H-tetrazol-5- ylmethyl)-amino]-thiazol-4-one

16 4-(2-{5-[1-(2,4-Bis- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one

17 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(2- [1,2,4]triazol-1-yl-ethylamino)- thiazol-4-one

18 5-[1-(4-Methoxy-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2- [1,2,4]triazol-1-yl-ethylamino)-thiazol-4-one

19 4-(2-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one

20 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (pyridin-3-ylamino)-thiazol- 4-one

21 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (pyrrolidin-3S-ylamino)-thiazol- 4-one

22 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1-(2- hydroxy-ethyl)-piperidin-4-ylamino]-thiazol-4-one

23 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [(pyridin-3-ylmethyl)-amino]- thiazol-4-one

24 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2- imidazol-1-yl-ethylamino)- thiazol-4-one

25 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1- methyl-piperidin-4-ylamino)- thiazol-4-one

26 2-(1-Aza-bicyclo[2.2.2]oct- 3(R)-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

27 2-(1-Aza-bicyclo[2.2.2]oct- 3(S)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

28 2-(1-Aza-bicyclo[2.2.2]oct- 3(R)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

29 2-(1-Aza-bicyclo[2.2.2]oct- 3(S)-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-thiazol- 4-one

30 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5- ylmethyl)-amino]-thiazol-4-one

31 2-{5-[1-(2,4-Bis- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-ethanesulfonic acid amide

32 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [(pyrimidin-5-ylmethyl)-amino]- thiazol-4-one

33 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-[2-(tetrahydro- pyran-4-yl)-ethylamino]- thiazol-4-one

34 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-[2-(2-oxo- pyrrolidin-1-yl)-ethylamino]- thiazol-4-one

35 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5- methyl-4H-[1,2,4]triazol-3-ylmethyl)-amino]-thiazol-4-one

36 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methyl-4H- [1,2,4]triazol-3-ylmethyl)-amino]-thiazol-4-one

37 4-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}- butyricacid

38 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2- hydroxy-1-hydroxymethyl-ethylamino)-thiazol-4-one

39 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(4- methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one

40 2-(Azetidin-3-ylamino)-5-[1- (2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5- ylmethylene]-thiazol-4-one

41 2-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-N-methyl-acetamide

42 5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(1H- [1,2,3]triazol-4-ylmethyl)-amino]-thiazol-4-one

43 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-[(1H- [1,2,3]triazol-4-ylmethyl)- amino]-thiazol-4-one

44 (S,S)-4-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylic acid

45 1-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic acid

46 4-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyric acid

47 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2- {[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}-1,3-thiazol-4(5H)- one

48 5-({1-[2,4- Bis(trifluoromethyl)benzyl]-3- iodo-1H-indazol-5-yl}methylidene)-2-{[2-(4- methylpiperazin-1-yl)ethyl]amino}-1,3-thiazol- 4(5H)-one

C) Synthesis

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Schemes 1 and 2 describe suggestedsynthetic routes. Using the scheme, the guidelines below, and theexamples, a person of skill in the art may develop analogous or similarmethods for a given compound that is within the invention. These methodsare representative of the synthetic schemes, but are not to be construedas limiting the scope of the invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, geometric isomers, and enantiomers thereof areencompassed within the scope of the present invention.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Examples of the described synthetic routes include Schemes 1 and 2,Examples 1 through 48, and General Procedures A-G. Compounds analogousto the target compounds of these examples can be made according tosimilar routes. The disclosed compounds are useful as pharmaceuticalagents as described herein.

Abbreviations or acronyms useful herein include:

-   -   AIBN (2,2′-Azobisisobutyronitrile)    -   Boc (tert butyl carbamate)    -   BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexyluorophosphate)    -   BuLi (butyllithium)    -   Cbz (Benzyl carbamate)    -   DIBAL-H (Diisobutylaluminum hydride)    -   DCM (Dichloromethane)    -   DIPEA (Diisopropylethylamine)    -   DMAP (4-(dimethylamino)pyridine)    -   DME (Ethylene glycol dimethyl ether)    -   DMF (dimethylformamide)    -   DMPU (1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)    -   DMSO (methyl sulfoxide)    -   EDC (N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide)    -   EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride)    -   Et (ethyl)    -   EtOAc (ethyl acetate)    -   h or hr (hour(s))    -   HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate)    -   HCl (Hydrochloric acid)    -   HMPA (Hexamethylphosphoramide)    -   HOBt (1-Hydroxybenzotriazole monohydrate)    -   HPLC (High Performance Liquid Chromatography)    -   LCMS (high pressure liquid chromatography with mass        spectrometer)    -   LDA (Lithium diisopropylamide)    -   LHMDS (lithium hexamethyl disilazide)    -   Me (methyl)    -   MeCN (acetonitrile)    -   MeOH (methyl alcohol)    -   MOM (Methoxymethyl)    -   NaHMDS (sodium hexamethyl disilazide)    -   NaO_(t)Bu (sodium tert-butoxide)    -   NBS (N-Bromosuccinimide)    -   NMP (N-Methyl Pyrrolidinone)    -   N,N-DMA (N,N-dimethylacetamide)    -   rt or RT (room temperature)    -   SPE (solid phase extraction)    -   TBTU (O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate)    -   TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical)    -   TFA (trifluoroacetic acid);    -   THF (tetrahydrofuran)    -   TLC (thin layer chromatography)

General Guidance

The compounds of Formula (I), wherein X, R₁, R₂, R₃ and R₄ are definedas in Formula I, may be synthesized as outlined by the general syntheticroute illustrated in Scheme 1. Treatment of an appropriate1H-Indazole-5-carbaldehyde II and an appropriate substituted benzyl oran appropriate substituted alkylheteroaryl (C₁alkylaryl) III, a knowncompound or compound prepared by known methods, wherein Y is a suitablyselected leaving group such as Cl, Br, I, tosylate, mesylate, and thelike, both of which are either commercially available or can be madefrom commercially available starting materials, with a base such asK₂CO₃, Cs₂CO₃, NaH, and the like, in a solvent such as NMP, DMF, THF,and the like, at a temperature preferably between 25-150° C. can providethe substituted 1-Benzyl-1H-indazole-5-carbaldehyde IV. Knoevenagelreaction of aldehyde IV with a suitably compound of formula V in thepresence of a catalytic amount of base such as piperidine and an acidsuch as benzoic acid can provide compound VI. The Knoevenagel reactionis typically performed in an aprotic solvent such as toluene at atemperature preferably between 100-200° C. The reaction between aldehydeIV and compound V may also be performed with a base such as sodiumacetate in a solvent such as acetonitrile at a temperature preferablybetween 50-150° C., or in the presence of ammonium acetate in aceticacid at a temperature preferably between 50-150° C. The compound offormula VI is reacted with a compound of formula R_(a)Y, a knowncompound or compound prepared by known methods, wherein R_(a) is asuitably selected alkyl such as methyl, ethyl, isopropyl, and the like,and Y, a suitably selected leaving group such as Cl, Br, I, tosylate,mesylate, and the like, in the presence of a base such as K₂CO₃, Et₃N,DIPEA, and the like, in an organic solvent such as MeOH, MeCN, DCM, THF,and the like, at a temperature preferably between 25-80° C., to yieldthe corresponding compound of formula VII. Treatment of VII with anappropriate amine R₄—NH₂ in a solvent such as acetonitrile, MeOH, DMF,and the like, at a temperature preferably between 25-180° C. can providecompounds of Formula (I).

In the case where the amine of formula R₄—NH₂ incorporates anotherprotected nitrogen such as Boc, Cbz, and the like, this nitrogen may bedeprotected under appropriate conditions known to those skilled in theart to afford a compound of formula I of the present invention. Forexample, Boc-protected amines may be deprotected under acidic conditionsusing reagents such as HCl, TFA, and the like. Likewise, Cbz-protectedamines may be deprotected under acidic conditions or hydrogenolysis.

The compounds of Formula (I), wherein X, R₁, R₂, R₃ and R₄ are definedas in Formula I, may alternatively be synthesized as outlined by thegeneral synthetic route illustrated in Scheme 2. Accordingly, a suitablecompound of formula V, a known compound or compound prepared by knownmethods, is reacted with a compound of formula R_(a)Y, a known compoundor compound prepared by known methods, wherein R_(a) is a suitablyselected alkyl such as methyl, ethyl, isopropyl, and the like, and Y, asuitably selected leaving group such as Cl, Br, I, tosylate, mesylate,and the like, in the presence of a base such as K₂CO₃, Et₃N, DIPEA, andthe like, in an organic solvent such as MeOH, DCM, THF, and the like, ata temperature preferably between 25-100° C., to yield the correspondingcompound of formula VIII. Treatment of VIII with an appropriate amineR₄—NH₂ in a solvent such as acetonitrile, MeOH, DMF, and the like, at atemperature preferably between 25-150° C. can provide compounds ofFormula IX. Knoevenagel reaction of aldehyde IV with a suitably compoundof formula IX in the presence of a catalytic amount of base such aspiperidine and an acid such as benzoic acid can provide compounds ofFormula (I). The Knoevenagel reaction is typically performed in anaprotic solvent such as toluene at a temperature preferably between100-200° C. The reaction between aldehyde IV and a suitably compound offormula IX may also be performed with a base such as sodium acetate in asolvent such as acetonitrile at a temperature preferably between 50-150°C., or in the presence of ammonium acetate in acetic acid at atemperature preferably between 50-150° C.

In the case where the amine of formula R₄—NH₂ incorporates anotherprotected nitrogen such as Boc, Cbz, and the like, this nitrogen may bedeprotected under appropriate conditions known to those skilled in theart to afford a compound of formula I of the present invention. Forexample, Boc-protected amines may be deprotected under acidic conditionsusing reagents such as HCl, TFA, and the like. Likewise, Cbz-protectedamines may be deprotected under acidic conditions or hydrogenolysis.

EXAMPLES General Procedure A

A solution of 1H-Indazole-5-carbaldehyde (7.6 g, 52.0 mmol) and anappropriate substituted benzyl bromide (62.1 mmol) in DMF (120 mL) wastreated with Cs₂CO₃ (17 g, 52.1 mmol), and the mixture was heated in anoil bath at 100° C. for 16 h. The reaction was cooled to RT andpartitioned between EtOAc and H₂O. The organic phase was washed withwater (3×), brine, dried over Na₂SO₄ and concentrated in vacuo. Silicagel chromatography (EtOAc/hexanes) afforded the desired isomer.Recrystallization of the desired isomer from EtOAc/Hexanes afforded thedesired pure aldehyde isomer.

General Procedure B

2-thioxo-thiazolidin-4-one (0.59 g, 4.42 mmol) and aldehyde fromProcedure A (4.42 mmol) were dissolved in toluene (40 mL) and treatedwith benzoic acid (0.22 mmol) and piperidine (0.22 mmol). The flask wasequipped with a Dean-Stark trap, and the reaction was refluxed at 130°C. using an oil bath for 16 h. After cooling to RT, the product wascollected by filtration and washed with toluene and water to afford thedesired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneproduct.

A mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one(0.32 mmol) and DIPEA (0.63 mmol) in DCM (5 mL) was treated with anappropriate iodoalkane (1 mmol). The reaction mixture was stirred at RTfor 16 h and partitioned between DCM and H₂O. The organic phase waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo to affordthe desired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-oneproduct.

To a mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-one(0.31 mmol) and the appropriate primary amine (0.37 mmol) was addedMeOH/DCM (2:1 v/v, 8 mL). The suspension was heated at 70° C. underreflux conditions for 4 h. The reaction was cooled to RT and the solventconcentrated in vacuo. Silica gel chromatography or reverse phase HPLCafforded the desired pure product.

General Procedure C

To a mixture of 2-thioxo-thiazolidin-4-one (0.35 mmol) and aldehyde fromProcedure A (0.32 mmol) was added acetic acid (2.0 mL) and NH₄OAc (0.95mmol). The suspension was heated at 95° C. (aluminum heating block) for2 h. The product was collected by filtration, washed with cold ethanoland triturated with EtOAc/hexanes to afford the desired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneproduct.

A mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one(0.32 mmol) and DIPEA (0.63 mmol) in DCM (5 mL) was treated with anappropriate iodoalkane (1 mmol). The reaction mixture was stirred at RTfor 16 h and partitioned between DCM and H₂O. The organic phase waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo to affordthe desired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-oneproduct.

To a mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-one(0.31 mmol) and the appropriate primary amine (0.37 mmol) was addedMeOH/DCM (2:1 v/v, 8 mL). The suspension was heated at 70° C. underreflux conditions for 4 h. The reaction was cooled to RT and the solventconcentrated in vacuo. Silica gel chromatography or reverse phase HPLCafforded the desired pure product.

General Procedure D

2-thioxo-thiazolidin-4-one (10 g, 75 mmol) in aqueous 2% NaOH (200 mL)was treated with the appropriate iodoalkane (82.5 mmol). The reactionmixture was stirred at RT for 16 h and partitioned between DCM and H₂O.The organic phase was washed with a cold saturated NaHCO₃ solution, H₂O,dried over Na₂SO₄ and concentrated in vacuo to afford the desired pure2-alkylsulfanyl-thiazol-4-one product.

To a mixture of 2-alkylsulfanyl-thiazol-4-one (2.71 mmol) and theappropriate primary amine (2.71 mmol) was added EtOH (15 mL). Thesuspension was heated at 65° C. for 16 h. The reaction was cooled to RTand the solvent concentrated in vacuo. Silica gel chromatography(MeOH/DCM) afforded the desired pure 2-amino-thiazol-4-one product.

2-Amino-thiazol-4-one (1.33 mmol) and the aldehyde from Procedure A(1.33 mmol) were dissolved in toluene (16 mL) and treated with benzoicacid (0.07 mmol) and piperidine (0.07 mmol). The flask was equipped witha Dean-Stark trap, and the reaction was refluxed at 130° C. using an oilbath for 12 h. After cooling to RT, the product was collected byfiltration and triturated with hexanes to afford the desired pureproduct.

General Procedure E

2-thioxo-thiazolidin-4-one (10 g, 75 mmol) in aqueous 2% NaOH (200 mL)was treated with the appropriate iodoalkane (82.5 mmol). The reactionmixture was stirred at RT for 16 h and partitioned between DCM and H₂O.The organic phase was washed with a cold saturated NaHCO₃ solution, H₂O,dried over Na₂SO₄ and concentrated in vacuo to afford the desired pure2-alkylsulfanyl-thiazol-4-one product.

To a mixture of 2-alkylsulfanyl-thiazol-4-one (2.71 mmol) and theappropriate primary amine (2.71 mmol) was added EtOH (15 mL). Thesuspension was heated at 65° C. for 16 h. The reaction was cooled to RTand the solvent concentrated in vacuo. Silica gel chromatography(MeOH/DCM) or reverse phase HPLC afforded the desired pure2-amino-thiazol-4-one product.

To a mixture of 2-amino-thiazol-4-one (0.18 mmol) and aldehyde fromProcedure A (0.18 mmol) was added acetic acid (1.0 mL) and NH₄OAc (0.1mmol). The suspension was heated at 100° C. (aluminum heating block) for16 h and then diluted with water. The product was collected byfiltration and purified using Silica gel chromatography or reverse phaseHPLC to afford the desired pure product.

General Procedure F Deprotection of t-Butyl Carbamate BOC(CH₃)₃COC(O)Nusing trifluoroacetic acid

The BOC intermediate (1 mmol) was treated with TFA/DCM (0.3:0.7 v/v).The mixture was stirred at room temperature for 2-4 hr and concentratedin vacuo. The residue was partitioned between EtOAc and a saturatedaqueous NaHCO₃ solution. The organic phase was dried and evaporated toafford the desired product. Silica gel chromatography (DCM/EtOAc/MeOH)or reverse phase HPLC afforded the desired pure product.

General Procedure G Deprotection of t-Butyl Carbamate BOC(CH₃)₃COC(O)Nusing HCl

A solution of BOC intermediate (0.05 mmol) in MeOH (2 mL) and THF (1 mL)was treated with 4.0N HCl in 1,4-dioxane (2.5 mL) and stirred at roomtemperature for 12 hours. The solvent was removed in vacuo and theresidue recrystallized from methanol/diethyl ether to yield the desiredproduct Silica gel chromatography (DCM/EtOAc/MeOH) or reverse phase HPLCafforded the desired pure product.

Example 12-(3-Dimethylamino-propylamino)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

A. 1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared following General Procedure A

¹H NMR (CDCl₃): δ 10.09 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 7.96 (dd,1H), 7.47 (dd, 1H), 7.40 (d, 1H), 6.77 (dd, 1H), 5.86 (s, 2H).

LC/MS: mass calcd. for C₁₆H₁₀F₄N₂O (m/z), 322.2; found, 323.3 [M+H]⁺

B.2-(3-Dimethylamino-propylamino)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andN1,N1-Dimethyl-propane-1,3-diamine following General Procedure C.

¹H NMR (CDCl₃): δ 8.20 (m, 1H), 7.92-8.03 (2H), 7.52-7.59 (1H), 7.46 (m,1H), 7.33 (m, 1H), 7.06-7.11 (1H), 6.72-6.78 (1H), 5.81 (s, 2H), 3.87(t, 2H), 2.58 (m, 2H), 2.33 and 3.31 (s, total 6H), 1.80-1.93 (2H).

LC/MS: mass calcd. for C₂₄H₂₃F₄N₅OS: 505.16, found 506.4 [M+H]⁺

Example 25-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-dimethylamino-propylamino)-thiazol-4-one

A. 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-Indazole-5-carbaldehyde and1-bromomethyl-2,4-bis-trifluoromethyl-benzene following GeneralProcedure A.

¹H NMR (CDCl₃): δ 10.08 9s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 7.99 (s,1H), 7.95 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 1H), 6.82 (d, 1H), 5.91 (s,2H).

LC/MS: mass calcd. for C₁₇H₁₀F₆N₂O: 372.07, found 373.2 [M+H]⁺

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-onewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-thioxo-thiazolidin-4-one following General Procedure C.

LC/MS: mass calcd. for C₂₀H₁₁F₆N₄OS₂ (m/z), 487.0; found, 488.1 [M+H]⁺

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneand iodomethane following General Procedure C.

¹H NMR (DMSO): δ 8.4 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.02-7.96 (m,2H), 7.85 (d, 1H), 7.73 (dd, 1H), 6.92 (d, 1H), 5.99 (s, 2H), 2.85 (s,3H).

LC/MS (m/z) [M+1]⁺502.1 (calculated for C₂₁H₁₃F₆N₃OS₂, 501.04).

D.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-dimethylamino-propylamino)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand

N1,N1-Dimethyl-propane-1,3-diamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.28 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.85 (s,1H), 7.80 (d, 1H), 7.64 (m, 1H), 7.59 (m, 1H), 6.85 (d, 1H), 5.98 (s,2H), 3.64 (t, 2H), 2.43 (t, 2H), 2.28 (s, 6H), 1.87 (m, 2H).

LC/MS: mass calcd. for C₂₅H₂₃F₆N₅OS: 555.15, found 556.4 [M+H]⁺

Example 35-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-dimethylamino-propylamino)-thiazol-4-one

A. 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-indazole-5-carbaldehyde and1-bromomethyl-4-chloro-2-trifluoromethyl-benzene following GeneralProcedure A.

LC/MS: mass calcd. for C₁₆H₁₀ClF₃N₂O (m/z), 338.71; found, 339.1 [M+H]⁺

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-dimethylamino-propylamino)-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andN1,N1-Dimethyl-propane-1,3-diamine following General Procedure C.

¹H NMR (CDCl₃): δ 8.18 (m, 1H), 7.89-7.99 (2H), 7.71 (m, 1H), 7.51 (m,1H), 7.28-7.35 (2H), 6.66 (d, 1H), 5.78 (s, 2H), 3.85 (t, 2H), 2.58 (m,2H), 2.33 and 2.29 (s, total 6H), 1.78-1.90 (2H).

LC/MS: mass calcd. for C₂₄H₂₃ClF₃N₅OS: 521.13, found 522.2 [M+H]⁺

Example 4{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-aceticacid

{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-aceticacid was prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andglycine following General Procedure C.

¹H NMR (CD₃OD): δ 8.24 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.78 (m,1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.47 (m, 1H), 6.68 (d, 1H), 5.85 (s,2H), 4.32 (s, 2H).

LC/MS: mass calcd. for C₂₁H₁₄ClF₃N₄O₃S: 494.04, found 495.2 [M+H]⁺

Example 55-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-morpholin-4-yl-ethylamino)-thiazol-4-one

A. 1-Bromomethyl-4-methoxy-2-trifluoromethyl-benzene A solution of(4-methoxy-2-trifluoromethyl-phenyl)-methanol (1.04 g, 5 mmol) in DCM(20 mL) was treated at 0° C. with phosphorous tribromide (1.64 g, 6mmol). The reaction mixture was stirred for 10 minutes at 0° C., 1 h atroom temperature. The solvent was evaporated in vacuo to yield a crudeoil which was purified via flash chromatography (10% DCM in hexane) toyield the title compound as an oil (1.36 g, 100%).

LC/MS: mass calcd. for C₉H₈BrF₃O (m/z), 269.06; found, 270 [M+H]⁺

B. 1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1-bromomethyl-4-methoxy-2-trifluoromethyl-benzene and1H-indazole-5-carbaldehyde following General Procedure A.

LC/MS: mass calcd. for C₁₇H₁₃F₃N₂O₂ (m/z), 334.2; found, 335.2 [M+H]⁺

C.5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-morpholin-4-yl-ethylamino)-thiazol-4-onewas prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-morpholin-4-yl-ethylamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.10 (s, 1H), 7.94 (s, 1H), 7.60 (m, 1H), 7.40 (m,1H), 7.23-7.29 (2H), 6.95 (m, 1H), 6.61 (m, 1H), 5.74 (s, 2H), 3.12-4.10(15H).

LC/MS: mass calcd. for C₂₆H₂₆F₃N₅O₃S: 545.17, found 546.2 [M+H]⁺

Example 65-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-pyrrolidin-1-yl-ethylamino)-thiazol-4-one

5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-pyrrolidin-1-yl-ethylamino)-thiazol-4-onewas prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-pyrrolidin-1-yl-ethylamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.10 (m, 1H), 7.91 (m, 1H), 7.59 (m, 1H), 7.39 (m,1H), 7.23-7.28 (2H), 6.94 (m, 1H), 6.61 (m, 1H), 5.73 (s, 2H), 3.79 (s,3H), 3.03-3.78 (8H), 1.97-2.22 (4H).

LC/MS: mass calcd. for C₂₆H₂₆F₃N₅O₂S: 529.18, found 530.2 [M+H]⁺

Example 75-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-thiazol-4-one

5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-thiazol-4-onewas prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-(3-amino-propyl)-pyrrolidin-2-one following General Procedure C.

¹H NMR (CDCl₃): δ 8.16 (m, 1H), 7.93 (m, 1H), 7.91 (s, 1H), 7.49 (m,1H), 7.32 (d, 1H), 7.23 (m, 1H), 6.87 (m, 1H), 6.67 (d, 1H), 5.76 (s,2H), 3.80 (s, 3H), 3.40-3.70 (6H), 2.49 (t, 2H), 1.85-2.14 (4H).

LC/MS: mass calcd. for C₂₇H₂₆F₃N₅O₃S: 557.17, found 558.2 [M+H]⁺

Example 85-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(2-hydroxy-ethoxy)-ethylamino]-thiazol-4-one

A. 1-(2,4-Dichloro-benzyl)-1H-indazole-5-carbaldehyde was prepared from1H-indazole-5-carbaldehyde and 1-bromomethyl-2,4-dichloro-benzenefollowing General Procedure A.

LC/MS: mass calcd. for C₁₅H₁₀Cl₂N₂O (m/z), 305.1; found, 305.1 [M+H]⁺

B.5-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(2-hydroxy-ethoxy)-ethylamino]-thiazol-4-onewas prepared from 1-(2,4-dichloro-benzyl)-1H-indazole-5-carbaldehyde and2-(2-amino-ethoxy)-ethanol following General Procedure C.

¹H NMR (CDCl₃): δ 8.15 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.52 (m,1H), 7.44 (m, 1H), 7.38 (m, 1H), 7.12 (m, 1H), 6.79 (d, 1H), 5.67 (s,2H), 3.63-3.97 (8H).

LC/MS: mass calcd. for C₂₂H₂₀Cl₂N₄O₃S: 490.06, found 491.1 [M+H]⁺

Example 92-(2S,3-Dihydroxy-propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(2S,3-Dihydroxy-propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and(S)-3-amino-propane-1,2-diol following General Procedure C.

¹H NMR (DMSO-d₆): δ 8.28 (s, 1H), 8.02 (s, 1H), 7.69-7.73 (2H), 7.59 (d,1H), 7.25 (s, 1H), 7.11 (d, 1H), 6.74 (d, 1H), 5.75 (s, 2H), 5.08 (m,1H), 4.76 (br, 2H), 3.77 (s, 3H), 3.64-3.71 (2H).

LC/MS: mass calcd. for C₂₃H₂₁F₃N₄O₄S: 506.12, found 507.3 [M+H]⁺

Example 102-(2R,3-Dihydroxy-propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(2R,3-Dihydroxy-propylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and(R)-3-amino-propane-1,2-diol following General Procedure C.

¹H NMR (DMSO-d₆): δ 8.28 (s, 1H), 8.02 (s, 1H), 7.69-7.73 (2H), 7.58 (d,2H), 7.25 (s, 1H), 7.11 (m, 1H), 6.74 (d, 1H), 5.75 (s, 2H), 5.09 (m,1H), 4.75 (br, 2H), 3.77 (s, 3H), 3.64-3.71 (2H).

LC/MS: mass calcd. for C₂₃H₂₁F₃N₄O₄S: 506.12, found 507.3 [M+H]⁺

Example 112-(2,2-Difluoro-ethylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(2,2-Difluoro-ethylamino)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2,2-difluoro-ethylamine following General Procedure C.

¹H NMR (DMSO-d₆): δ 8.29 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 7.72 (d,1H), 7.60 (d, 1H), 7.25 (m, 1H), 7.11 (m, 1H), 6.75 (d, 1H), 6.25 (t,1H), 5.76 (s, 2H), 3.77 (s, 3H), 3.30 (2H).

LC/MS: mass calcd. for C₂₂H₁₇F₆N₄O₂S: 496.10, found 497.3 [M+H]⁺

Example 125-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-morpholin-4-yl-ethylamino)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-morpholin-4-yl-ethylamino)-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-morpholin-4-yl-ethyl amine following General Procedure C.

¹H NMR (CDCl₃): δ 8.21 (m, 1H), 8.01 (m, 1H), 7.99 (m, 1H), 7.90-7.95(2H), 7.62 (m, 1H), 7.53 (m, 1H), 7.33 (m, 1H), 6.82 (m, 1H), 5.89 (m,2H), 3.54-3.85 (6H), 2.50-2.83 (6H).

LC/MS: mass calcd. for C₂₆H₂₃F₆N₅O₂S: 583.15, found 584.3 [M+H]⁺

Example 131-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid

1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid was prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-amino-cyclopropanecarboxylic acid following General Procedure C.

¹H NMR (CD₃OD): δ 8.22 (d, 1H), 8.05 (m, 1H), 7.83 (d, 1H), 7.61 (m,1H), 7.50 (d, 1H), 7.26 (m, 1H), 7.00 (m, 1H), 6.68 (d, 1H), 5.78 (s,2H), 3.80 (s, 3H), 1.59-1.67 (2H), 1.25-1.36 (2H).

LC/MS: mass calcd. for C₂₄H₁₉F₃N₄O₄S: 516.11, found 517.4 [M+H]⁺

Example 14

-   -   -   -   -   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylic                    acid

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid was prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-amino cyclopropane carboxylic acid following General Procedure C.

¹H NMR (CD₃OD): δ 8.29 (m, 1H), 8.10 (m, 1H), 8.05 (s, 1H), 7.87 (m,1H), 7.79 (m, 1H), 7.57-7.69 (2H), 6.85 (d, 1H), 5.98 (s, 2H), 1.65-2.12(2H), 1.22-1.53 (2H).

LC/MS: mass calcd. for C₂₄H₁₆F₆N₄O₃S: 554.08, found 555.4 [M+H]⁺

Example 155-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2H-tetrazol-5-ylmethyl)-amino]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2H-tetrazol-5-ylmethyl)-amino]-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andC-(2H-tetrazol-5-yl)-methylamine following General Procedure C.

¹H NMR (DMSO-d₆): δ 10.33 (br, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 8.09 (s,1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.78 (s, 1H), 7.63 (d, 1H), 6.88 (d,1H), 5.96 (s, 2H), 5.04 (s, 2H).

LC/MS: mass calcd. for C₂₂H₁₄F₆N₈OS: 552.09, found 553.4 [M+H]⁺

Example 164-(2-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one

4-(2-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}ethyl)-piperazin-2-onewas prepared1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and4-(2-amino-ethyl)-piperazin-2-one following General Procedure C.

¹H NMR (CD₃OD): δ 8.28 (m, 1H), 8.08 (m, 1H), 8.06 (m, 1H), 7.85 (s,1H), 7.80 (m, 1H), 7.65 (m, 1H), 7.59 (d, 1H), 6.85 (d, 1H), 5.98 (s,2H), 3.77 (t, 1H), 3.20-3.48 (3H), 3.17 (s, 2H), 2.71-2.79 (4H).

LC/MS: mass calcd. for C₂₆H₂₂F₆N₆O₂S: 596.14, found 597.5 [M+H]⁺

Example 175-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-[1,2,4]triazol-1-yl-ethylamino)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-0,2,41-triazol-1-yl-ethylamino)-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-[1,2,4]-triazol-1-yl-ethylamine following General Procedure C.

¹H NMR of the major tautomer (CDCl₃): δ 8.26 (s, 1H), 8.20 (s, 1H),7.97-8.00 (3H), 7.89 (s, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.36 (m, 1H),6.84 (m, 1H), 5.90 (s, 2H), 4.86 (t, 1H), 4.53 (m, 1H), 4.21 (m, 1H),3.99 (t, 1H).

LC/MS: mass calcd. for C₂₄H₁₇F₆N₇OS: 565.11, found 566.4 [M+H]⁺

Example 185-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-[1,2,4]triazol-1-yl-ethylamino)-thiazol-4-one

5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-[0,2,4]-triazol-1-yl-ethylamino)-thiazol-4-onewas prepared from1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-[1,2,4]-triazol-1-yl-ethylamine following General Procedure C.

¹H NMR (CDCl₃): δ 8.26 (s, 1H), 8.20 (m, 1H), 7.96-7.97 (2H), 7.88 (s,1H), 7.50 (m, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 6.88 (m, 1H), 6.73 (m,1H), 5.77 (s, 2H), 4.87 (br, 2H), 3.99 (br, 2H), 3.81 (s, 3H).

LC/MS: mass calcd. for C₂₄H₂₀F₃N₇O₂S: 527.14, found 528.5 [M+H]⁺

Example 194-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one

4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and4-(2-amino-ethyl)-piperazin-2-one following General Procedure C.

¹H NMR (CD₃OD): δ 8.26 (m, 1H), 8.08 (m, 1H), 7.93 (s, 1H), 7.81 (s,1H), 7.64 (m, 1H), 7.58 (m, 1H), 7.49 (m, 1H), 6.70 (m, 1H), 5.87 (s,2H), 4.03 (s, 2H), 3.58-3.81 (4H), 3.09-3.14 (4H).

LC/MS: mass calcd. for C₂₅H₂₂ClF₃N₆O₂S: 562.12, found 563.5 [M+H]⁺

Example 205-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyridin-3-ylamino)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyridin-3-ylamino)-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andpyridin-3-ylamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.65-8.69 (2H), 8.37 (m, 1H), 8.22 (s, 1H), 8.10 (m,1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.45-7.59 (3H), 6.69 (d,1H), 5.85 (s, 2H).

LC/MS: mass calcd. for C₂₄H₁₅ClF₃N₅OS: 513.06, found 514.3 [M+H]⁺

Example 215-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one

A.3-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester following GeneralProcedure C.

LC/MS: mass calcd. for C₂₈H₂₇ClF₃N₅O₃S: 605.15, found 606.1 [M+H]⁺

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-onewas prepared from3-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pyrrolidine-1-carboxylicacid tert-butyl ester following General Procedure F.

¹H NMR (CDCl₃): δ 8.21 (s, 1H), 8.01 (s, 1H), 7.86-7.93 (1H), 7.69-7.73(1H), 7.48-7.58 (1H), 7.28-7.37 (2H), 6.59-6.71 (1H), 5.79 and 5.75 (s,total 2H), 4.18 (br, 1H), 2.90-3.48 (4H), 2.00-2.41 (2H).

LC/MS: mass calcd. for C₂₃H₁₉ClF₃N₅OS: 505.15, found 506.5 [M+H]⁺

Example 225-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1-(2-hydroxy-ethyl)-piperidin-4-ylamino]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1-(2-hydroxy-ethyl)-piperidin-4-ylamino]-thiazol-4-oneester was prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-(4-Amino-piperidin-1-yl)-ethanol following General Procedure C.

¹H NMR (CD₃OD): δ 8.24 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.79 (m,1H), 7.60 (m, 1H), 7.54 (d, 1H), 7.47 (m, 1H), 6.66 (d, 1H), 5.84 (s,2H), 4.03 (m, 1H), 3.69 (t, 2H), 3.00 (m, 2H), 2.56 (t, 2H), 2.24 (t,2H), 2.07 (m, 2H), 1.69 (m, 2H).

LC/MS: mass calcd. for C₂₆H₂₆ClF₃N₆O₂S: 563.14, found 564.5 [M+H]⁺

Example 235-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyridin-3-ylmethyl)-amino]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyridin-3-ylmethyl)-amino]-thiazol-4-oneester was prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andC-pyridin-3-yl-methylamine following General Procedure C.

¹H NMR (DMSO-d₆): δ 8.60 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.08 (s,1H), 7.89 (m, 1H), 7.78 (m, 3H), 7.64 (m, 2H), 7.43 (m, 1H), 6.75 (d,1H), 5.86 (s, 2H), 4.78 (s, 2H).

LC/MS: mass calcd. for C₂₅-H₁₇ClF₃N₆OS: 527.08, found 528.4 [M+H]⁺

Example 245-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-imidazol-1-yl-ethylamino)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-imidazol-1-yl-ethylamino)-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-Imidazol-1-yl-ethylamine following General Procedure C.

¹H NMR of the major tautomer (CDCl₃): δ 8.15 (s, 1H), 7.91 (s, 1H), 7.88(s, 1H), 7.70 (s, 1H), 7.47 (m, 1H), 7.26-7.34 (4H), 6.90 (s, 1H), 6.64(d, 1H), 5.76 (s, 2H), 4.31 (m, 2H), 4.02 (m, 2H).

LC/MS: mass calcd. for C₂₄H₁₈ClF₃N₆OS: 530.09, found 531.4 [M+H]⁺

Example 255-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1-methyl-piperidin-4-ylamino)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1-methyl-piperidin-4-ylamino)-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-methyl-piperidin-4-ylamine following General Procedure C.

¹H NMR (CDCl₃): δ 8.19 (m, 1H), 7.92-8.00 (2H), 7.71 (s, 1H), 7.48-7.56(1H), 7.33 (m, 2H), 6.66 (m, 1H), 5.80 (s, 2H), 4.23 and 3.44 (m, total1H), 2.86 (m, 2H), 2.31 (3H), 1.92-2.19 (4H), 1.52-1.73 (2H).

LC/MS: mass calcd. for C₂₅H₂₃ClF₃N₅OS: 533.13, found 534.4 [M+H]⁺

Example 262-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-aza-bicyclo[2.2.2]oct-3(R)-ylamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.29 (m, 1H), 8.08 (br, 2H), 7.84 (s, 1H), 7.81 (d,1H), 7.65 (m, 1H), 7.60 (d, 1H), 6.88 (d, 1H), 5.98 (s, 2H), 3.38-4.90(4H), 2.71-3.00 (4H), 1.56-2.17 (4H).

LC/MS: mass calcd. for C₂₇H₂₃F₆N₅OS: 579.15, found 580.5 [M+H]⁺

Example 272-(1-Aza-bicyclo[2.2.2]oct-3(S)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(1-Aza-bicyclo[2.2.2]oct-3(S)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-aza-bicyclo[2.2.2]oct-3(S)-ylamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.27 (m, 1H), 8.08 (m, 1H), 7.89 (s, 1H), 7.82 (m,1H), 7.64 (dd, 1H), 7.57 (d, 1H), 7.50 (dd, 1H), 6.71 (d, 1H), 5.87 (s,2H), 3.15-4.90 (8H), 1.96-2.50 (4H).

LC/MS: mass calcd. for C₂₆H₂₃ClF₃N₅OS: 545.13, found 546.5 [M+H]⁺

Example 282-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-aza-bicyclo[2.2.2]oct-3(R)-ylamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.25 (m, 1H), 8.05 (s, 1H), 7.80 (m, 2H), 7.63 (m,1H), 7.55 (d, 1H), 7.48 (m, 1H), 6.67 (d, 1H), 5.86 (s, 2H), 3.34-4.80(4H), 2.68-2.93 (4H), 1.53-2.11 (4H).

LC/MS: mass calcd. for C₂₆H₂₃ClF₃N₅OS: 545.13, found 546.5 [M+H]⁺

Example 292-(1-Aza-bicyclo[2.2.2]oct-3(S)-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(1-Aza-bicyclo[2.2.2]oct-3(S)-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-aza-bicyclo[2.2.2]oct-3(S)-ylamine following General Procedure C.

¹H NMR (CD₃OD): δ 8.30 (s, 1H), 8.08 (m, 2H), 7.86 (s, 1H), 7.82 (m,1H), 7.67 (m, 1H), 7.61 (m, 1H), 6.88 (d, 1H), 6.00 (s, 2H), 3.44-4.80(4H), 2.74-2.99 (4H), 1.58-2.16 (4H).

LC/MS: mass calcd. for C₂₇H₂₃F₆N₅OS: 579.15, found 580.5 [M+H]⁺

Example 305-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-one

A. 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-Indazole-5-carbaldehyde and1-bromomethyl-2,4-bis-trifluoromethyl-benzene following GeneralProcedure A.

¹H NMR (CDCl₃): δ 10.08 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 7.99 (s,1H), 7.95 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 1H), 6.82 (d, 1H), 5.91 (s,2H).

LC/MS (m/z) [M+1]⁺373.2 (calculated for C₁₇H₁₀F₆N₂O, 372.07).

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-onewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-thioxo-thiazolidin-4-one following General Procedure B.

¹H NMR (CDCl₃): δ 10.08 9s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 7.99 (s,1H), 7.95 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 1H), 6.82 (d, 1H), 5.91 (s,2H).

LC/MS (m/z) [M+1]⁺488.1 (calculated for C₂₀H₁₁F₆N₄OS₂, 487.0).

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneand iodomethane following General Procedure B.

¹H NMR (DMSO): δ 8.4 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.02-7.96 (m,2H), 7.85 (d, 1H), 7.73 (dd, 1H), 6.92 (d, 1H), 5.99 (s, 2H), 2.85 (s,3H)

LC/MS (m/z) [M+1]⁺502.1 (calculated for C₂₁ H₁₃F₆N₃OS₂, 501.04).

D.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand C-pyrimidin-5-yl-methylamine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 10.12 (bs, 1H), 9.16 (s, 1H), 8.86-8.84 (m,2H), 8.37 (s, 1H), 8.10 (d, 2H), 7.97 (d, 1H), 7.83-7.80 (m, 2H), 7.65(dd, 1H), 6.88 (d, 1H), 5.97 (s, 2H), 4.80 (s, 2H)

LC/MS (m/z) [M+1]⁺563.2 (calculated for C₂₅H₁₆F₆N₆OS, 562.1).

Example 312-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethanesulfonicacid amide

2-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethanesulfonicacid amide was prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-amino-ethanesulfonic acid amide following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 9.82 (bs, 1H), 8.37 (s, 1H), 8.10 (d, 2H), 7.97(d, 1H), 7.83-7.87 (m, 2H), 7.65 (dd, 1H), 7.03 (s, 2H), 6.89 (d, 1H),5.98 (s, 2H), 3.89 (bs, 2H), 3.37 (t, 2H)

LC/MS (m/z) [M+1]⁺578.2 (calculated for C₂₂H₁₇F₆N₅O₃S₂, 577.07).

Example 325-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-one

A. 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-indazole-5-carbaldehyde and1-bromomethyl-4-chloro-2-trifluoromethyl-benzene following GeneralProcedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.07 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H),7.94 (dd, 1H), 7.73 (d, 1H), 7.38-7.33 (m, 2H), 6.66 (d, 1H), 5.82 (s,2H)

LC/MS (m/z) [M+1]⁺339.1 (calculated for C₂₅H₂₃ClF₃N₅O₃S₂, 338.71).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-onewas prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-indazole-5-carbaldehyde and 2-thioxo-thiazolidin-4-onefollowing General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.15 (s, 1H), 7.89 (d, 1H),7.82-7.79 (m, 2H), 7.67-7.65 (m, 2H), 6.77 (d, 1H), 5.87 (s, 2H)

LC/MS (m/z) [M+1]⁺454.0 (calculated for C₂₅H₂₃ClF₃N₅O₃S₂, 453.89).

C.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneand iodomethane following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.89(d, 1H), 7.81 (d, 1H), 7.72 (dd, 1H), 6.66 (dd, 1H), 6.78 (d, 1H), 5.87(s, 2H), 2.85 (s, 3H)

LC/MS (m/z) [M+1]⁺468.3 (calculated for C₂₀H₁₅ClF₃N₃OS₂, 469.93).

D.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-oneand C-Pyrimidin-5-yl-methylamine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 10.12 (bs, 1H), 9.15 (s, 1H), 8.86-8.84 (m,2H), 8.34 (s, 1H), 8.08 (s, 2H), 7.89 (d, 1H), 7.81-7.77 (m, 2H),7.66-7.62 (m, 2H), 6.73 (d, 1H), 5.86 (s, 2H), 4.79 (s, 2H)

LC/MS (m/z) [M+1]⁺529.2 (calculated for C₂₄H₁₆ClF₃N₆OS, 528.07).

Example 335-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(tetrahydro-pyran-4-yl)-ethylamino]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(tetrahydro-pyran-4-yl)-ethylamino]-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-(tetrahydro-pyran-4-yl)-ethylamine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 9.62 (bs, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 8.00(s, 1H), 7.97 (d, 1H), 7.82-7.75 (m, 2H), 7.64 (dd, 1H), 6.89-6.87 (m,1H), 5.98 (s, 2H), 3.86-3.82 (m, 2H), 3.58-3.56 (m, 2H), 3.30-3.24 (m,2H), 1.62-1.53 (m. 5H), 1.20-1.16 (m, 2H).

LC/MS (m/z) [M+1]⁺583.2 (calculated for C₂₇H₂₄F₆N₄O₂S, 582.15).

Example 345-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(tetrahydro-pyran-4-yl)-ethylamino]-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-(2-amino-ethyl)-pyrrolidin-2-one following General Procedure B.

¹H NMR (400 MHz, DMSO) (5 9.70-9.67 (m, 1H), 8.37 (s, 1H), 8.12 (s, 1H),8.08 (s, 1H), 7.97-7.96 (m, 1H), 7.82-7.76 (m, 2H), 7.64 (dd, 1H), 6.88(d, 1H), 5.98 (s, 2H), 3.69-3.65 (m, 2H), 3.44-3.38 (m, 4H), 2.19-2.15(m. 2H), 1.92-1.88 (m, 2H).

LC/MS (m/z) [M+1]⁺582.2 (calculated for C₂₆H₂₁F₆N₅O₂S, 581.13).

Example 355-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-amino]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methyl-4H-[1,2,4]-triazol-3-ylmethyl)-amino]-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andC-(5-methyl-4H-[1,2,4]-triazol-3-yl)-methylamine following GeneralProcedure B.

¹H NMR (400 MHz, DMSO) (5 10.11-10.09 (m, 1H), 8.35-8.33 (m, 1H), 8.07(s, 1H), 7.89-7.88 (m, 1H), 7.80-7.76 (m, 2H), 7.66-7.62 (m, 2H), 7.74(d, 1H), 5.86 (s, 2H), 4.71-4.69 (m, 2H), 2.35 (bs, 3H).

LC/MS (m/z) [M+1]⁺532.1 (calculated for C₂₃H₁₇ClF₃N₇OS, 531.09).

Example 365-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-amino]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-amino]-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andC-(5-methyl-4H-[1,2,4]triazol-3-yl)-methylamine following GeneralProcedure B.

¹H NMR (400 MHz, DMSO) δ 10.15-10.11 (m, 1H), 8.38 (s, 1H), 8.13-8.08(m, 2H), 7.97 (d, 1H), 7.83-7.76 (m, 2H), 7.66-7.63 (m, 2H), 6.88 (d,1H), 5.98 (s, 2H), 4.72-4.70 (m, 2H), 2.33 (bs, 3H).

LC/MS (m/z) [M+1]⁺566.1 (calculated for C₂₄H₁₇F₆N₇OS, 565.11).

Example 374-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid

4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid was prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and4-amino-butyric acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.12 and 8.05 (2s, 1H), 7.88 (d,1H), 7.79-7.73 (m, 2H), 7.70-7.61 (m, 2H), 6.75 and 6.72 (2d, 1H), 5.86(s, 2H), 3.53 (t, 2H), 2.28 (t, 2H), 1.84-1.77 (m, 2H).

LC/MS (m/z) [M+1]⁺523.1 (calculated for C₂₃H₁₈ClF₃N₄O₃S, 522.07).

Example 385-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-amino-propane-1,3-diol following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 9.60 (d, 1H), 8.34 (s, 1H), 8.12 and 8.05 (2s,1H), 7.89 (d, 1H), 7.80-7.69 (m, 2H), 7.69-7.62 (m, 2H), 6.75 and 6.73(2d, 1H), 5.86 (s, 2H), 4.94 (2, 2H), 4.13-4.08 (m, 1H), 3.62-3.54 (m,4H).

LC/MS (m/z) [M+1]⁺511.2 (calculated for C₂₂H₁₈ClF₃N₄O₃S, 510.07).

Example 395-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-(4-methyl-piperazin-1-yl)-ethylamine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.19-8.16 (m, 1H), 7.98-7.92 (m, 2H), 7.71 (s,1H), 7.57-7.49 (m, 1H), 7.34-7.29 (m, 2H), 6.67-6.63 (m, 1H), 5.78 (s,2H), 3.79 and 3.52 (2t, 2H), 2.74 and 2.66 (2t, 2H), 2.56 and 2.47 (2bs, 8H), 2.31 and 2.29 (2s, 3H).

LC/MS (m/z) [M+1]⁺563.2 (calculated for C₂₆H₂₆ClF₃N₆OS, 562.15).

Example 402-(Azetidin-3-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

A.3-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-azetidine-1-carboxylicacid tert-butyl ester was prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-10 carbaldehyde and3-amino-azetidine-1-carboxylic acid tert-butyl ester following GeneralProcedure C.

LC/MS: mass calcd. for C₂₈H₂₅F₆N₅O₃S: 625.16, found 526.1 [M+H]⁺

B.2-(Azetidin-3-ylamino)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from3-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-azetidine-1-carboxylicacid tert-butyl ester following General Procedure F.

¹H NMR (CD₃OD): 8.29 (s, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H),7.80 (d, 1H), 7.65 (d, 1H), 7.61 (d, 1H), 6.87 (d, 1H), 5.98 (s, 2H),4.92 (m, 1H), 4.47-4.36 (m, 4H).

LC/MS: mass calcd. for C₂₃H₁₇F₆N₅OS: 525.11, found 526.3 [M+H]⁺

Example 412-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-N-methyl-acetamide

2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-N-methyl-acetamidewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-amino-N-methyl-acetamide following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 9.92 (t, 1H), 8.35 (s, 1H), 8.11-8.07 (m, 2H),7.89 (s, 1H), 7.80-7.75 (m, 2H), 7.66-7.62 (m, 2H), 6.73 (d, 1H), 5.86(s, 2H), 4.17 and 4.16 (2s, 2H), 2.64 and 2.63 (2s, 3H).

LC/MS (m/z) [M+1]⁺508.0 (calculated for C₂₂H₁₇ClF₃N₅O₂S, 507.07).

Example 425-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-thiazol-4-onewas prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andC-(1H-[1,2,3]triazol-4-yl)-methylamine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 10.08 (t, 1H), 8.34 (s, 1H), 8.06 (m, 2H), 7.88(d, 1H), 7.79-7.77 (m, 2H), 7.66-7.62 (m, 2H), 6.73 (d, 1H), 5.86 (s,2H), 4.83 and 4.82 (2s, 2H).

LC/MS (m/z) [M+1]⁺518.1 (calculated for C₂₂H₁₅ClF₃N₇OS, 517.07).

Example 435-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-thiazol-4-onewas prepared from1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andC-(1H-[1,2,3]triazol-4-yl)-methylamine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 10.09 (t, 1H), 8.37 (s, 1H), 8.16-8.08 (m, 2H),7.97 (d, 1H), 7.82-7.78 (m, 2H), 7.64 (dd, 1H), 6.88 (d, 1H), 5.98 (s,2H), 4.83 and 4.82 (2s, 2H).

LC/MS (m/z) [M+1]⁺552.1 (calculated for C₂₃H₁₅F₆N₇OS, 551.1).

Example 444-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid

(S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid was prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and4-amino-cyclohexanecarboxylic acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 9.56 (d, 1H), 8.33 (s, 1H), 8.14-8.06 (m, 1H),7.89 (d, 1H), 7.80-7.74 (m, 2H), 7.66-7.62 (m, 2H), 6.77 and 6.72 (2d,1H), 5.86 (s, 2H), 4.10-4.08 (m, 1H), 2.46 (bs, 1H), 1.92-1.86 (m, 2H),1.79-1.74 (m, 2H), 1.68-1.59 (m, 4H).

LC/MS (m/z) [M+1]⁺563.1 (calculated for C₂₆H₂₂ClF₃N₄O₃S, 562.11).

Example 451-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid was prepared from1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-amino-cyclopropanecarboxylic acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.37 and 8.35 (2s, 1H),8.12-8.08 (m, 1H), 7.89 (d, 1H), 7.81-7.77 (m, 2H), 7.69-7.63 (m, 2H),6.77-6.73 (m, 1H), 5.86 (s, 2H), 1.62-1.59 (m, 1H), 1.52-1.48 (m, 1H),1.42 (bs, 1H), 1.28-1.25 (m, 1H)

LC/MS (m/z) [M+1]⁺521.0 (calculated for C₂₃H₁₆ClF₃N₄O₃S, 520.06).

Example 464-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid

A.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneand iodopropane following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.99-7.98 (m, 2H), 7.71 (d, 1H),7.53 (dd, 1H), 7.35-7.32 (m, 2H), 6.66 (d, 1H), 5.79 (s, 2H), 3.42 (t,2H), 1.91-1.82 (m, 2H), 1.07 (t, 3H).

LC/MS (m/z) [M+1]⁺496.1 (calculated for C₂₂H₁₇ClF₃N₃OS₂, 495.97).

B.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-amino-3-hydroxy-butyric acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 9.75 (t, 1H), 8.34-8.33 (m, 1H), 8.12 and 8.06(2s, 1H), 7.89 (d, 1H), 7.80-7.74 (m, 2H), 7.66-7.62 (m, 2H), 6.77-6.72(m, 1H), 5.86 (s, 2H), 4.12-4.10 (m, 1H), 3.63-3.59 (m, 1H), 3.50-3.47(m, 1H), 2.45 (dd, 1H), 2.30 (dd, 1H).

LC/MS (m/z) [M+1]⁺539.1 (calculated for C₂₃H₁₈ClF₃N₄O₄S, 538.07).

Example 47 JNJ-42259789(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}-1,3-thiazol-4(5H)-one

A.3-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-4-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 3-Amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺622.5 (calculated for C₂₈H₂₇ClF₃N₅O₄S, 621.14).

B.(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}-1,3-thiazol-4(5H)-onewas prepared from3-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-4-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester following General Procedure F.

¹H NMR (CD₃OD): δ 8.18 and 8.13 (s, 1H, rotamer), 7.98 and 7.89 (s, 1H,rotamer), 7.77 (s, 1H), 7.75 and 7.73 (m, 1H, rotamer), 7.38-7.57 (3H),6.62 and 6.56 (d, 1H, rotamer), 5.78 and 5.76 (s, 2H, rotamer),4.52-4.61 (1H), 4.35 and 4.04 (m, 1H, rotamer), 3.86 and 3.77 (dd, 1H,rotamer), 3.54-3.68 (2H), 3.37-3.43 (1H).

LC/MS (m/z) [M+1]⁺522.5 (calculated for C₂₃H₁₉ClF₃N₅O₂S, 521.95).

Example 48 JNJ-423476955-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one

A. 2-[2-(4-Methyl-piperazin-1-yl)ethylamino]-thiazol-4-one was preparedfrom 2-Methylsulfanyl-thiazol-4-one and2-(4-Methyl-piperazin-1-yl)-ethylamine following general procedure E.

¹H NMR (400 MHz, CDCl₃) δ 3.98 and 3.92 (2s, 2H, rotamers), 3.68 (t,1H), 3.49 (s, 2H), 3.39 (t, 1H), 2.66 (t, 1H), 2.60 (t, 1H), 2.53-2.47(m, 7H), 2.31-2.30 (m, 3H).

LC/MS (m/z) [M+1]⁺243.2 (calculated for C₁₀H₁₈N₄OS, 242.12).

B. 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehydewas prepared from 3-Iodo-1H-indazole-5-carbaldehyde and1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following generalprocedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.09 (dd, 1H), 8.01-7.99 (m,2H), 7.66 (d, 1H), 7.34 (d, 1H), 6.91 (d, 1H), 5.91 (s, 2H).

LC/MS (m/z) [M+1]⁺497.9 (calculated for C₁₇H₉F₆₁N₂O, 497.97).

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-onewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and2-[2-(4-Methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one followingGeneral Procedure E.

¹H NMR (400 MHz, CD₃OD) δ 8.06 (s, 1H), 7.83-7.81 (m, 2H), 7.69-7.67 (m,2H), 7.59 (dd, 1H), 6.96 (d, 1H), 5.97 (s, 2H), 3.78 (t, 2H), 3.37-3.28(m, 6H), 2.88-2.85 (m, 4H), 2.80-2.77 (m, 4H).

LC/MS (m/z) [M+1]⁺722.9 (calculated for C₂₇H₂₅F₆₁N₆OS, 722.08).

D) General Administration, Formulation, and Dosages

The present compounds are ERR-α modulators and are therefore useful intreating, ameliorating or inhibiting the progression of ERR-α mediatedconditions including but not limited to ankylosing spondylitis,artherosclerosis, arthritis (such as rheumatoid arthritis, infectiousarthritis, childhood arthritis, psoriatic arthritis, reactivearthritis), bone-related diseases (including those related to boneformation), breast cancer (including those unresponsive to anti-estrogentherapy), cardiovascular disorders, cartilage-related disease (such ascartilage injury/loss, cartilage degeneration, and those related tocartilage formation), chondrodysplasia, chondrosarcoma, chronic backinjury, chronic bronchitis, chronic inflammatory airway disease, chronicobstructive pulmonary disease, diabetes, disorders of energyhomeostasis, gout, pseudogout, lipid disorders, metabolic syndrome,multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta,osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease,periodontal disease, polymyalgia rheumatica, Reiter's syndrome,repetitive stress injury, hyperglycemia, elevated blood glucose level,and insulin resistance and other disorders, diseases, or conditionsrelated thereto.

The invention features a method for treating a subject with an ERR-amediated disease, said method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. In particular, the inventionalso provides a method for treating or inhibiting the progression ofbreast cancer, arthritis, inflammatory airway disease, or metabolicdisorders, and associated symptoms or complications thereof in asubject, wherein the method comprises administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Some of the crystalline forms for the compounds may exist as polymorphsand as such are intended to be included in the present invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents, and such solvates are intended tobe encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography.

The compounds may be prepared in racemic form or as individualenantiomers or diasteomers by either stereospecific synthesis or byresolution. The compounds may, for example, be resolved into theircomponent enantiomers or diastereomers by standard techniques, such asthe formation of stereoisomeric pairs by salt formation with anoptically active base, followed by fractional crystallization andregeneration of the free acid. The compounds may also be resolved byformation of stereoisomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.It is to be understood that all stereoisomers, racemic mixtures,diastereomers, cis-trans isomers, and enantiomers thereof areencompassed within the scope of the present invention.

E) Use

1. Dosages

Those of skill in the treatment of disorders, diseases, or conditionsmediated by ERR-α can determine the effective daily amount from the testresults presented hereinafter and other information. The exact dosageand frequency of administration depends on the particular compound ofinvention used, the particular condition being treated, the severity ofthe condition being treated, the age, weight and general physicalcondition of the particular patient as well as other medication thepatient may be taking, as is well known to those skilled in the art.Furthermore, it is evident that said effective daily amount may belowered or increased depending on the response of the treated patientand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. The effective daily amount rangesmentioned herein are therefore only guidelines in practicing the presentinvention.

Preferably, the method for the treatment of the ERR-a disordersdescribed in the present invention using any of the compounds as definedherein, the dosage form will contain a pharmaceutically acceptablecarrier containing between from about 0.1 mg to about 5000 mg;particularly from about 0.5 mg to about 1000 mg; and, more particularly,from about 1 mg to about 100 mg of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Thedosages, however, may be varied depending upon the requirement of thesubjects, the severity of the condition being treated and the compoundbeing employed. The use of either daily administration or post-periodicdosing may be employed.

The pharmaceutical compositions herein will contain, per unit dosageunit, e.g., tablet, capsule, powder, injection, suppository, teaspoonfuland the like, of from about 0.001 mg/kg/day to about 10 mg/kg/day(particularly from about 0.01 mg/kg/day to about 1 mg/kg/day; and, moreparticularly, from about 0.1 mg/kg/day to about 0.5 mg/kg/day) and maybe given at a dosage of from about 0.001 mg/kg/day to about 30 mg/kg/day(particularly from about 0.01 mg/kg/day to about 2 mg/kg/day, moreparticularly from about 0.1 mg/kg/day to about 1 mg/kg/day and even moreparticularly from about 0.5 mg/kg/day to about 1 mg/kg/day).

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, dry powders for reconstitution or inhalation,granules, lozenges, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, autoinjector devices orsuppositories for administration by oral, intranasal, sublingual,intraocular, transdermal, parenteral, rectal, vaginal, dry powderinhaler or other inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection.

For preparing solid pharmaceutical compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and gildants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like.

Suitable gildants include, but are not limited to, talc, cornstarch,silica (i.e. CAB-O-SIL™ silica available from Cabot, SYLOID™ silicaavailable from W.R. Grace/Davison, and AEROSIL™ silica available fromDegussa) and the like. Sweeteners and flavorants may be added tochewable solid dosage forms to improve the palatability of the oraldosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active form of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate, cellulose acetate trimetllitate), polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate and ethylacrylatecopolymers, methacrylate and methyl methacrylate copolymers and thelike. Sustained release tablets may also be made by film coating or wetgranulation using slightly soluble or insoluble substances in solution(which for a wet granulation acts as the binding agents) or low meltingsolids a molten form (which in a wet granulation may incorporate theactive ingredient). These materials include natural and syntheticpolymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and thelike), esters of fatty acids metallic soaps, and other acceptablematerials that can be used to granulate, coat, entrap or otherwise limitthe solubility of an active ingredient to achieve a prolonged orsustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.1 mg to about 5000 mg;preferably, the dose will be in the range of from about 1 mg to about100 mg per day for an average human. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated. Advantageously, acompound of the present invention may be administered in a single dailydose or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedby those skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, andthe advancement of the disease condition. In addition, factorsassociated with the particular subject being treated, including subjectage, weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level. The above dosagesare thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as ERR-a modulators is required for a subject in needthereof.

2. Formulations

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. Methods of formulatingpharmaceutical compositions have been described in numerous publicationssuch as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revisedand Expanded, Volumes 1-3, edited by Lieberman et al; PharmaceuticalDosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al;and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, editedby Lieberman et al; published by Marcel Dekker, Inc.

3. Combination Therapy

The compounds of the present invention may be used in combination withone or more pharmaceutically active agents. These include anti-diabeticagents, anti-obesity agents, other lipid lowering agents, directthrombin inhibitor (DTI), as well as lipid lowering agents such asstatin drugs and the fibrates.

Other agents useful for the combination therapy of the present inventioninclude glucokinase modulators include:

Anti-diabetic agents include RXR modulators such as:

-   -   (1) bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455);    -   (2) 9-cis-retinoic acid;    -   (3) AGN-4326 (also known as ALRT-4204, AGN-4204, ALRT-326,        ALRT-324, or LGD 1324);    -   (4) LGD 1324 (ALRT 324);    -   (5) LG 100754;    -   (6) LY-510929;    -   (7) LGD 1268        (6-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-ylcycloprop-1-yl)nicotinic        acid, known as ALRT 268 or LG 100268); and    -   (8) LG 100264.

Anti-diabetic agents also include thiazolidinedione andnon-thiazolidinedione insulin sensitizers, which decrease peripheralinsulin resistance by enhancing the effects of insulin at target organsand tissues.

The following agents are known to bind and activate the nuclear receptorperoxisome proliferator-activated receptor-gamma (PPARγ) which increasestranscription of specific insulin-responsive genes. Examples ofPPAR-gamma agonists are thiazolidinediones such as:

-   -   (1) rosiglitazone        (2,4-thiazolidinedione,5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-,        (Z)-2-butenedioate (1:1) or        5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as AVANDIA; also known as BRL 49653, BRL 49653C, BRL        49653c, SB 210232, or rosiglitazone maleate);    -   (2) pioglitazone (2,4-thiazolidinedione,        5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-,        monohydrochloride, (+−)- or        5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methy)-2,4-thiazolidinedione,        known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U        72107, U 72107A, U 72107E, pioglitazone hydrochloride (USAN));    -   (3) troglitazone        (5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl -2H        -1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as NOSCAL, REZULIN, ROMOZIN, or PRELAY; also known as        CI-991, CS 045, GR 92132, GR 92132X);    -   (4)        ((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazolidinedione        or 5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl        -2,4-thiazolidinedione or        5-(6-(2-fluorobenzyloxy)naphthalen-2-ylmethyl)thiazolidine-2,4-dione,        also known as MCC-555 or neoglitazone); and    -   (5) 5-BTZD.

Additionally, the non-thiazolidinediones that act as insulin sensitizingagents include, but are not limited to:

-   -   (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU 182716:        isoxazolidine-3,5-dione, 4-((4-(2-phenyl        -5-methyl)-1,3-oxazolyl)ethylphenyl -4)methyl-);    -   (2) KRP-297        (5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(trifluoromethyl)benzyl)benzamide        or 5-((2,4-dioxo        -5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide);        and    -   (3) Farglitazar (L-tyrosine,        N-(2-benzoylphenyl)-o-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-        or        N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-L-tyrosine,        or GW2570 or GI-262570).

Other anti-diabetic agents have also been shown to have PPAR modulatoractivity such as PPAR gamma, SPPAR gamma, and/or PPAR delta/gammaagonist activity. Examples are listed below:

-   -   (1) AD 5075;    -   (2) R 119702        ((+−)-5-(4-(5-Methoxy-1H-benzimidazol-2-ylmethoxy)benzyl)        thiazolin-2,4-dione hydrochloride, or CI 1037 or CS 011);    -   (3) CLX-0940 (peroxisome proliferator-activated receptor alpha        agonist/peroxisome proliferator-activated receptor gamma        agonist);    -   (4) LR-90 (2,5,5-tris (4-chlorophenyl)-1,3-dioxane-2-carboxylic        acid, PPARdelta/γ agonist);    -   (5) Tularik (PPARγ agonist);    -   (6) CLX-0921 (PPARγ agonist);    -   (7) CGP-52608 (PPAR agonist);    -   (8) GW-409890 (PPAR agonist);    -   (9) GW-7845 (PPAR agonist);    -   (10) L-764406 (PPAR agonist);    -   (11) LG-101280 (PPAR agonist);    -   (12) LM-4156 (PPAR agonist);    -   (13) Risarestat (CT-112);    -   (14) YM 440 (PPAR agonist);    -   (15) AR-H049020 (PPAR agonist);    -   (16) GW 0072        (4-(4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)        butyl)benzoic acid);    -   (17) GW 409544 (GW-544 or GW-409544);    -   (18) NN 2344 (DRF 2593);    -   (19) NN 622 (DRF 2725);    -   (20) AR-H039242 (AZ-242);    -   (21) GW 9820 (fibrate);    -   (22) GW 1929        (N-(2-benzoylphenyl)-O-(2-(methyl-2-pyridinylamino)ethyl)-L-tyrosine,        known as GW 2331, PPAR alpha/γ agonist);    -   (23) SB 219994        ((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)benzenepropanoic        acid or        3-(4-1-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2(S)-(2,2,2-trifluoroethoxy)propionic        acid or benzenepropanoic        acid,4-(2-(2-benzoxazolylmethylamino))-alpha-(2,2,2-trifluoroethoxy)-,        (alphaS)-, PPARalpha/γ agonist);    -   (24) L-796449 (PPAR alpha/γ agonist);    -   (25) Fenofibrate (Propanoic acid,        2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester,        known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR alpha        agonist);    -   (26) GW-9578 (PPAR alpha agonist);    -   (27) GW-2433 (PPAR alpha/γ agonist);    -   (28) GW-0207 (PPARγ agonist);    -   (29) LG-100641 (PPARγ agonist);    -   (30) LY-300512 (PPARγ agonist);    -   (31) NID525-209 (NID-525);    -   (32) VDO-52 (VDO-52);    -   (33) LG 100754 (peroxisome proliferator-activated receptor        agonist);    -   (34) LY-510929 (peroxisome proliferator-activated receptor        agonist);    -   (35) bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455); and    -   (36) GW-1536 (PPAR alpha/γ agonist).

Other insulin sensitizing agents include, but are not limited to:

-   -   (1) INS-1 (D-chiro inositol or        D-1,2,3,4,5,6-hexahydroxycyclohexane);    -   (2) protein tyrosine phosphatase 1 B (PTP-1B) inhibitors;    -   (3) glycogen synthase kinase-3 (GSK3) inhibitors;    -   (4) beta 3 adrenoceptor agonists such as ZD 2079        ((R)—N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenethyl)        ammonium chloride, also known as ICI D 2079) or AZ 40140;    -   (5) glycogen phosphorylase inhibitors;    -   (6) fructose-1,6-bisphosphatase inhibitors;    -   (7) chromic picolinate, vanadyl sulfate (vanadium oxysulfate);    -   (8) KP 102 (organo-vanadium compound);    -   (9) chromic polynicotinate;    -   (10) potassium channel agonist NN 414;    -   (11) YM 268 (5, 5′-methylene-bis(1,4-phenylene)bismethylenebis        (thiazolidine-2,4-dione);    -   (12) TS 971;    -   (13) T 174        ((+−)-5-(2,4-dioxothiazolidin-5-ylmethyl)-2-(2-naphthylmethyl)benzoxazole);    -   (14) SDZ PGU 693        ((+)-trans-2(S-((4-chlorophenoxy)methyl)-7alpha-(3,4-dichlorophenyl)tetrahydropyrrolo(2,1-b)        oxazol-5 (6H)-one);    -   (15) S15261        ((−)-4-(2-((9H-fluoren-9-ylacetyl)amino)ethyl)benzoic acid        2-((2-methoxy-2-(3-(trifluoromethyl)phenyl)ethyl)amino) ethyl        ester);    -   (16) AZM 134 (Alizyme);    -   (17) ARIAD;    -   (18) R 102380;    -   (19) PNU 140975 (1-(hydrazinoiminomethyl)hydrazino)acetic acid;    -   (20) PNU 106817 (2-(hydrazinoiminomethyl)hydrazino)acetic acid;    -   (21) NC 2100        (5-((7-(phenylmethoxy)-3-quinolinyl)methyl)-2,4-thiazolidinedione;    -   (22) MXC 3255;    -   (23) MBX 102;    -   (24) ALT 4037;    -   (25) AM 454;    -   (26) JTP 20993        (2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl)-malonic        acid dimethyl diester);    -   (27) Dexlipotam (5(R)-(1,2-dithiolan-3-yl)pentanoic acid, also        known as (R)-alpha lipoic acid or (R)-thioctic acid);    -   (28) BM 170744 (2,2-Dichloro-12-(p-chlorophenyl)dodecanoic        acid);    -   (29) BM 152054        (5-(4-(2-(5-methyl-2-(2-thienyl)oxazol-4-yl)ethoxy)benzothien        -7-ylmethyl)thiazolidine-2, 4-dione);    -   (30) BM 131258        (5-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzothien        -7-ylmethyl)thiazolidine-2, 4-dione);    -   (31) CRE 16336 (EML 16336);    -   (32) HQL 975        (3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2(S)-(propylamino)propionic        acid);    -   (33) DRF 2189 (5-((4-(2-(1-Indolyl)ethoxy)phenyl)methyl)        thiazolidine-2,4-dione);    -   (34) DRF 554158;    -   (35) DRF-NPCC;    -   (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901;    -   (37) IkappaB Kinase (IKK B) Inhibitors;    -   (38) mitogen-activated protein kinase (MAPK) inhibitors    -   p38 MAPK Stimulators;    -   (39) phosphatidyl-inositide triphosphate;    -   (40) insulin recycling receptor inhibitors;    -   (41) glucose transporter 4 modulators;    -   (42) TNF-α antagonists;    -   (43) plasma cell differentiation antigen-1 (PC-1) Antagonists;    -   (44) adipocyte lipid-binding protein (ALBP/aP2) inhibitors;    -   (45) phosphoglycans;    -   (46) Galparan;    -   (47) Receptron;    -   (48) islet cell maturation factor;    -   (49) insulin potentiating factor (IPF or insulin potentiating        factor-1);    -   (50) somatomedin C coupled with binding protein (also known as        IGF-BP3, IGF-BP3, SomatoKine);    -   (51) Diab II (known as V-411) or Glucanin, produced by Biotech        Holdings Ltd. or Volque Pharmaceutical;    -   (52) glucose-6 phosphatase inhibitors;    -   (53) fatty acid glucose transport protein;    -   (54) glucocorticoid receptor antagonists; and    -   (55) glutamine:fructose-6-phosphate amidotransferase (GFAT)        modulators.

Anti-diabetic agents can further include biguanides, which decreasesliver glucose production and increases the uptake of glucose. Examplesof biguanides include metformin such as:

-   -   (1) 1,1-dimethylbiguanide (e.g., Metformin-DepoMed,        Metformin-Biovail Corporation, or METFORMIN GR (metformin        gastric retention polymer)); and    -   (2) metformin hydrochloride (N,N-dimethylimidodicarbonimidic        diamide monohydrochloride), also known as LA 6023, BMS 207150,        GLUCOPHAGE, or GLUCOPHAGE XR.

Additionally, anti-diabetic agents include alpha-glucosidase inhibitors,which inhibit alpha-glucosidase. Alpha-glucosidase converts fructose toglucose, thereby delaying the digestion of carbohydrates. The undigestedcarbohydrates are subsequently broken down in the gut, reducing thepost-prandial glucose peak. Examples of alpha-glucosidase inhibitorsinclude, but are not limited to:

-   -   (1) acarbose (D-glucose, O-4,6-dideoxy-4-(((1S        -(1alpha,4alpha,5beta,6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-,        also known as AG-5421, Bay -g-542, BAY-g-542, GLUCOBAY, PRECOSE,        GLUCOR, PRANDASE, GLUMIDA, or ASCAROSE);    -   (2) Miglitol (3,4,5-piperidinetriol,        1-(2-hydroxyethyl)-2-(hydroxymethyl)-, (2R (2alpha, 3beta,        4alpha, 5beta))- or        (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl        -3,4,5-piperidinetriol, also known as BAY 1099, BAY M 1099,        BAY-m-1099, BAYGLITOL, DIASTABOL, GLYSET, MIGLIBAY, MITOLBAY,        PLUMAROL);    -   (3) CKD-711        (0-4-deoxy-4-((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose);    -   (4) emiglitate        (4-(2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl)ethoxy)benzoic        acid ethyl ester, also known as BAY o 1248 or MKC 542);    -   (5) MOR 14 (3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-methyl-,        (2R -(2alpha,3beta,4alpha,5beta))-, also known as        N-methyldeoxynojirimycin or N-methylmoranoline); and    -   (6) Voglibose        (3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-D-epi-inositol        or        D-epi-Inositol,3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-,        also known as A 71100, AO 128, BASEN, GLUSTAT, VOGLISTAT.

Anti-diabetic agents also include insulins such as regular orshort-acting, intermediate-acting, and long-acting insulins,non-injectable or inhaled insulin, tissue selective insulin,glucophosphokinin (D-chiroinositol), insulin analogues such as insulinmolecules with minor differences in the natural amino acid sequence andsmall molecule mimics of insulin (insulin mimetics), and endosomemodulators. Examples include, but are not limited to:

-   -   (1) Biota;    -   (2) LP 100;    -   (3) (SP -5-21)-oxobis (1-pyrrolidinecarbodithioato-S, S′)        vanadium,    -   (4) insulin aspart (human insulin (28B-L-aspartic acid) or        B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID,        NOVOMIX, or NOVOLOG);    -   (5) insulin detemir (Human        29B-(N-6-(1-oxotetradecyl)-L-lysine)-(1A -21A), (1B        -29B)-Insulin or NN 304);    -   (6) insulin lispro (“28B-L-lysine -29B-L-proline human insulin,        or Lys(B28), Pro(B29) human insulin analog, also known as        lys-pro insulin, LY 275585, HUMALOG, HUMALOG MIX 75/25, or        HUMALOG MIX 50/50);    -   (7) insulin glargine (human (A21-glycine, B31-arginine,        B32-arginine) insulin HOE 901, also known as LANTUS, OPTISULIN);    -   (8) Insulin Zinc Suspension, extended (Ultralente), also known        as HUMULIN U or ULTRALENTE;    -   (9) Insulin Zinc suspension (Lente), a 70% crystalline and 30%        amorphous insulin suspension, also known as LENTE ILETIN II,        HUMULIN L, or NOVOLIN L;    -   (10) HUMULIN 50/50 (50% isophane insulin and 50% insulin        injection);    -   (11) HUMULIN 70/30 (70% isophane insulin NPH and 30% insulin        injection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill,        NOVOLIN 70/30 Prefilled;    -   (12) insulin isophane suspension such as NPH ILETIN II, NOVOLIN        N, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N;    -   (13) regular insulin injection such as ILETIN II Regular,        NOVOLIN R, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled,        HUMULIN R, or Regular U-500 (Concentrated);    -   (14) ARIAD;    -   (15) LY 197535;    -   (16) L-783281; and    -   (17) TE-17411.

Anti-diabetic agents can also include insulin secretion modulators suchas:

-   -   (1) glucagon-like peptide-1 (GLP-1) and its mimetics;    -   (2) glucose-insulinotropic peptide (GIP) and its mimetics;    -   (3) exendin and its mimetics;    -   (4) dipeptidyl protease (DPP or DPPIV) inhibitors such as        -   (4a) DPP-728 or LAF 237            (2-pyrrolidinecarbonitrile,1-(((2-((5-cyano-2-pyridinyl)amino)ethyl)amino)acetyl),            known as NVP -DPP-728, DPP-728A, LAF-237);        -   (4b) Sitagliptin, also known as Januvia;        -   (4c) Saxagliptin;        -   (4d) Linagliptin;        -   (4e) Alogliptin;        -   (4f) KRP-104;        -   (4g) AMG-222;        -   (4h) P 3298 or P32/98            (di-(3N-((2S,3S)-2-amino-3-methyl-pentanoyl)-1,3-thiazolidine)            fumarate);        -   (4i) TSL 225            (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic            acid);        -   (4j) Valine pyrrolidide (valpyr);        -   (4k) 1-aminoalkylisoquinolinone-4-carboxylates and analogues            thereof;        -   (4i) SDZ 272-070 (1-(L-Valyl)pyrrolidine);        -   (4m) TMC-2A, TMC-2B, or TMC-2C;        -   (4n) Dipeptide nitriles (2-cyanopyrrolodides);        -   (4o) CD26 inhibitors; and        -   (4p) SDZ 274-444.    -   (5) GPR119 modulators;    -   (6) glucagon antagonists such as AY-279955; and    -   (7) amylin agonists which include, but are not limited to,        pramlintide (AC-137, Symlin, tripro-amylin or pramlintide        acetate).

Other anti-diabetic agents have also been shown to have sodium glucosecotransporter-2 (SGLT-2) inhibition activity. Examples are listed below:

-   -   (1) Dapagliflozin;    -   (2) Remogliflozin;    -   (3) TA-7284;    -   (4) LX-4211;    -   (5) BI-44847;    -   (6) BI-10773;    -   (7) ASP-1941; and    -   (8) ISIS 388626.

Well-known anti-diabetic agents include insulin, sulfonylureas,biguanides, meglitinides, AGI's (Alpha-Glucosidase Inhibitors; e.g.,Glyset), PPAR alpha agonists, and PPAR gamma agonists, and dual PPARalpha/gamma agonists.

Anti-obesity agents can be classified into several categories based uponthe mechanism of action. These agents include selective serotoninreuptake inhibitors (SSRIs), serotonin agonists, serotonin andnorepinephrine reuptake inhibitors, pancreatic lipase inhibitors,β3-adrenoreceptor agonists, NPY antagonists, melanocortin receptoragonists, leptin-targeted agents, CB1 antagonists (e.g. Rimonabant),monoamine reuptake inhibotors (e.g. Sibutramine), microsomaltriglyceride transfer protein (MTP) inhibitors and lipase inhibitors(e.g. Orlistat).

Serotonin agonist agents such as dexfenfluramine and fenfluramine werereported to cause cardiac valvular abnormalities when used at theprescribed dosage in combination with phentermine. Selective serotoninreuptake inhibitors (SSRIs) are generally used for the treatment ofdepression. These agents include fluoxetine (Prozac), paroxetine,fluvoxamine and sertraline.

Representative serotonin modulators are listed below:

-   -   (A) Selective Serotonin Reuptake Inhibitors (SSRIs)        -   1. Citalopram (1-(3-(dimethylamino)            propyl)-1-(4-fluorophenyl)            -1,3-dihydro-5-isobenzofurancarbonitrile, also known as            citalopram hydrobromide (USAN), nitalopram, nitalapram, ZD            211, LU 10171, Lu10-171, LU 10171-B, CIPRAMIL, SEROPRAM,            CIPRAM, ELOPRAM, LUPRAM, SEPRAM, PRISDAL, or CELEXA);        -   2. Fluoxetine (benzenepropanamine,            N-Methyl-gamma-[4-(trifluoromethyl)phenoxy]-, (±)            hydrochloride, also known as LY 110140, RENEURON, SARAFEM,            or PROZAC);        -   3. Fluvoxamine            (5-methoxy-1-(4-(trifluoromethyl)phenyl)-1-pentanone            (E)-O-(2-aminoethyl) oxime, also known as fluvoxamine            maleate (USAN), DU 23000, MK 264, SME 3110, FEVARIN,            FLOXYFRAL, LUVOX, DUMYROX, DUMIROX, FLAVOXYL, FAVERIN, or            DEPROMEL);        -   4. Indeloxazine ((+,−)-2-((indel-7-yloxy)methyl) morpholine,            also known as ideloxazine, YM 08054, CI-874, ELEN, or NOIN);        -   5. Paroxetine hydrochloride            ((3S,4R)-3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine            hydrochloride, or piperidine,            3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-,            (3S-trans)-, also known as FR 7051, FG-7051, BRL 29060, BRL            29060A, NNC 207051, S1211103, CASBOL, SEROXAT, AROPAX,            PAXIL, TAGONIS, FROSINOR, DEROXAT, SEREUPIN, MOTIVAN, or            PAXIL CR);        -   6. Sertraline (1-naphthalenamine,            4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-,            (1S-cis)- or            1-Naphthalenamine,4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-methyl-,            (1S-cis), also known as CP 51974, CP 51974 01, AREMIS,            BESITRAN, GLADEM, LUSTRAL, SERAD, SERLAIN, SERLIFT, TATIG,            or ZOLOFT);        -   7. Tianeptine (7-((3-chloro-6,11-dihydro-6-methyldibenzo            (c, f) (1,2) thiazepin-11-yl)amino)heptanoic acid            S,S-dioxide, also known as S1574, or STABLON);        -   8. Centpropazine            (1-(p-propionylphenoxy)-3-(Nsup(4)-henylpiperazynyl)-propan-2-ol);        -   9. Paroxetine (GEOMATRIX drug delivery system)            (piperidine,3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-,            (3S-trans)-, also known as paroxetine, GEOMATRIX, PAXIL CR);        -   10.Escitalopram ((1S)-1-(3-(dimethylamino)            propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran            carbonitrile, or            5-Isobenzofurancarbonitrile,1-(3-(dimethylamino)            propyl)-1-(4-fluorophenyl)-1,3-dihydro-, (S)-, also known as            escitalopram, xalate (USAN), citalopram, (S)(+)-citalopram,            LU 26042, LU 26054, Lu26-054, or CIPRALEX);        -   11.Litoxetine (4-[(2-Naphthalenyl)methoxy]piperidine, also            known as SL 810385);        -   12.(S)-Fluoxetine            ((S)—N-methyl-gamma-(4-(trifluoromethyl)phenoxy)benzenepropanamine);        -   13.Cericlamine ((+,−)-3,4-dichloro-beta-(dimethylamino)-beta            -methylbenzenepropanol, also known as JO 1017(+,−), JO            1239(−), or JO 1240(+));        -   14.Dapoxetine            ((+)-(S)—N,N-dimethyl-alpha-(2-(1-naphthyl-oxy)ethyl)benzylamine            HCl, also known as LY-210448 or LY-243917);        -   15.6-Nitroquipazine derivatives;        -   16.Series of substituted 6-nitroquipazines (Pharmaprojects            No. 3391);        -   17.AAL 13 (2-(4-(3-chloropropyl)-1-piperazinyl) quinoline);        -   18.Depression therapy (by Vita Invest, Spain);        -   19.DUP 631 (C₁₃H₂₃NO₂S);        -   20.FI 4503 (by Ferrer, Spain);        -   21.Series of indolylcyclohexylamines (Pharmaprojects No.            6443, American Home Products);        -   22.LY 280253            (N-Methyl-N-[3[4-(methylthio)phenoxy)-3-phenylpropyl]amine);        -   23.LY 285974 (by Lilly);        -   24.Omiloxetine            (Ethanone,2-((3R,4S)-3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1-piperidinyl)-1-(4-fluorophenyl)-,            rel-, also known as FI-4500, FI-4501, FI-4503); and        -   25.WF 31            (8-Methyl-2beta-propanoyl-3beta-(4-(1-methylethyl)-phenyl)-8-azabicyclo[3.2.1]).    -   (B) Serotonin Agonists and Partial Agonists        -   1. Dexfenfluramine; and        -   2. Fenfluramine;    -   (C) Serotonin Reuptake Inhibitor with Serotonin Agonist Activity        -   1. EMD-68843 (2-benzofurancarboxamide,            5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)-1-piperazinyl)-, also            known as SB-659746-A);        -   2. OPC-14523 (2(1H)-quinolinone,            1-(3-(4-(3-chlorophenyl)-1-piperazinyl)            propyl)-3,4-dihydro-5-methoxy);        -   3. Vilazodone            (5-{4-[4-(5-Cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide,            also known as EMD 68843 or SB 659746A);        -   4. Series of condensed thiazoles (3-(benzo (b)            thiophen-3-yl)-5,6-dihydroimidazo            (2,1-b)thiazolemonohydrobromide dihydrate, Pharmaprojects            No. 5274, Abbott); and        -   5. VN-2222 (VN-8522, by Vita Invest, Spain).

Preferred examples of serotonin modulators include selective serotoninreuptake inhibitors such as Citalopram, Fluoxetine, Fluvoxamine,Indeloxazine, Paroxetine hydrochloride, Sertraline, Tianeptine,Centpropazine, Paroxetine, Escitalopram, and Litoxetine.

The following are also anti-obesity agents useful in the combinationtherapies of the present invention:

-   -   (A) Amylin and Amylin Analogs        -   1. Pramlintide            (I-Lysyl-I-cysteinyl-I-asparaginyl-I-threonyl-I            -alanyl-I-threonyl-I-cysteinyl-I-alanyl-I-threonyl-I            -glutaminyl-I-arginyl-I-leucyl-I-alanyl-I-asparaginyl-I            -phenylalanyl-I-leucyl-I-valyl-I-histidyl-I-seryl-I-seryl-I            -asparaginyl-I-asparaginyl-I-phenylalanylglycyl-I-prolyl-I            -isoleucyl-I-leucyl-I-prolyl-I-prolyl-I-threonyl-I            -asparaginyl-I-valylglycyl-I-seryl-I-asparaginyl-I-threonyl-I-tyrosinamide            cyclic (2-7)-disulfide, also known as pramlintide acetate,            AC 137, ACO 137, AC 0137, SYMLIN, Tripro-amylin, or            NORMYLIN);        -   2. Amylin agonists;        -   3. ACO 253 (AC 253, GG 747, GR 1150747A, or ANTAM);    -   (B) Ciliary Neurotrophic Factors (CNTF)        -   1. AXOKINE;        -   2. PEG-AXOKINE;        -   3. Peptide mimic of ciliary neurotrophic factor (CNTF mimic,            also known as MYELOS);        -   4. Ciliary neurotrophic factor (CNTF by Fidia, Italy);    -   (C) Glucagon-Like Peptide-1        -   1. AC-2993 (also known as exendin-4, AC-2993 LAR, Medisord            Exendin, AC-2993, Medisorb, or extendin-4, Amylin);        -   2. Exendin 4            (His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide,            also known as AC 2993, AC 2993 LAR, Medisord Exendin, or            AC-2993, Medisorb);        -   3. GLP-1 (Glucagon-like peptide-17-36 amide);        -   4. Glucagon-like peptide-1 oral transmucosal formulation;        -   5. Exendin 3            (His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide);    -   (D) Leptin & Leptin Mimetics        -   1. Leptin (2nd-generation);        -   2. Leptin agonists;        -   3. Leptin expression modulators;        -   4. Leptin signalling pathway modulators;        -   5. Leptin modulator;        -   6. Leptin (by IC Innovations, UK);        -   7. Leptin receptor, Monoclonal antibodies;        -   8. Recombinant native leptin;        -   9. LY-355101;        -   10. Leptin, Amylin    -   (E) Melanocortin Receptor Agonist (MC4)        -   1. HP-228 (Glycinamide, N-acetyl-L-norleucyl-L-glutaminyl-L            -histidyl-D-phenylalanyl-L-arginyl-D-tryptophyl-);        -   2. Melanocortin-4 receptor agonist (by Palatin, USA);        -   3. Melanocortin 4 agonist (by Pharmacopeia, Roche);        -   4. MC-4 agonists (by Millennium, Chiron);        -   5. Melanocortin-4 agonist (by Melacure Therapeutics,            Sweden);        -   6. Melanocortin receptor modulators (Pharmaprojects No.            5224, Neurocrine Biosciences, US);        -   7. Pharmaprojects No. 5967, Trega/Novartis;    -   (F) NPY Antagonists        -   1. AXC 0216;        -   2. AXC 1829;        -   3. SA-0204 (Neuropeptide Y antagonist, Apoptosis stimulator,            Lipid metabolism modulator);        -   4. Alpha-trinositol (D-myo-Inositol, 1,2,6-tris(dihydrogen            phosphate), also known as PP-56);        -   5. H 40922 (H 409/22);        -   6. BMS-192548 (1,11            (4H,5H)-naphthacenedione,2-acetyl-4-a,12a-dihydro-3,4-a,10,12,12a-pentahydroxy-8-methoxy-,            TAN 1612 isomer);        -   7. Alanex            (1,4-bis{(4-amino-6-methoxyphenylamino-1,2-dihydro-1,3,5-triazin-2-yl)-4-phenoxymethyl}benzene,            Neuropeptide Y derivatives);        -   8. PD-160170            (6-(2-isopropyl-benzenesulfonyl)-5-nitro-quinolin-8-ylamine);        -   9. 2,4-Diaminopyridine derivatives            (6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholino-2-(3-(2-propenyloxycarbonylamino)            benzylamino) pyridine, Pharmaprojects No. 5618,            Banyu/Merck);        -   10.Arpromidine analogs;        -   11. Neuropeptide Y antagonist (Pharmaprojects No. 4990,            Pfizer);        -   12.4 Methyl substituted benzimidazoles (NPY-1 antagonist,            NPY-2 antagonist);        -   13. LY-366337 (Neuropeptide Y1 antagonist);        -   14.S-2501, S-25579, S-25584, S-25585, S-19528, S-34354 (all            Neuropeptide Y1/5 antagonists);        -   15. Neuropeptide Y antagonist (subtypes 1 and 5) and Galanin            receptor antagonist (Pharmaprojects No. 4897, Bristol-Myers            Squibb);        -   16.Benzylamine derivatives            (1-arylpiperazinyl-1-alkyloxyphenyl-4-alkylcycloalkanes);        -   17.J-104870 (Neuropeptide Y1 antagonist, Appetite            suppressant);        -   18. LY-357897 (Neuropeptide Y1 antagonist);        -   19. Neuropeptide Y1 antagonist (Pfizer/Neurogen);        -   20.5R-120107A (Neuropeptide Y1 antagonist);        -   21. BIBO-3304            ((R)—N-((4-(aminocarbonylaminomethyl)-phenyl)methyl)-N2-(diphenylacetyl)-argininamide            trifluoroacetate);        -   22. BIBP 3226            ((R)—N-(4-((aminoiminomethyl)amino)-1-((((4-hydroxyphenyl)methyl)amino)carbonyl)butyl)-alpha-phenylbenzeneacetamide,            or benzeneacetamide,            N-((1R)-4-((aminoiminomethyl)amino)-1-((((4-hydroxyphenyl)methyl)amino)            carbonyl)butyl)-alpha-phenyl-);        -   23. SR 120819A (benzenepropanamide,            N-(1-((4-((((4-((dimethylamino)            methyl)cyclohexyl)methyl)amino)iminomethyl)phenyl)methyl)-2-oxo-2-(1-pyrrolidinyl)ethyl)-alpha-((2-naphthalenylsulfonyl)amino)-,            (alphaR-(N(R*(cis)), alphaR*))-);        -   24. NGD-95-1 (CP-422935, NGD 951);        -   25. Compounds with benzazepine nuclei (Neuropeptide Y1            antagonist);        -   26. Neuropeptide Y1 antagonist (by Yamanouchi            Pharmaceutical);        -   27. GI-264879A (Neuropeptide Y1 antagonist);        -   28. GW-1229 ([2′,4],[2,4′]homodimer of            Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH2, where Dpr is            diaminopropionic acid, also known as 1229U91, MN-24,            GR-231118);        -   29. BIIE-0246 (Cyclopentaneacetamide,            N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-1′-yl)-1-piperazinyl]-2-oxoethyl]-);        -   30. Neuropeptide Y2 antagonist (by Neurogen, USA);        -   31.Amide derivatives (Neuropeptide Y5 antagonist);        -   32. Neuropeptide Y agonist and antagonist-subtypes 1 and 5            (Schering-Plough);        -   33.            N-(sulfonamido)alkyl-[3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]amine            (RWJPRI);        -   34. Neuropeptide Y5 antagonist (by Novartis);        -   35. Neuropeptide Y5 antagonist (by Pfizer/Neurogen);        -   36. Pyrrolo[3,2-d]pyrimidine based neuropeptide Y5            antagonists;        -   37. CGP-71683 (Pharmaprojects No. 5651, CGP-71683A);        -   38. Neuropeptide Y5 agonist/antagonist (Pharmaprojects No.            5664, Bayer);    -   (G) Histamine H3 Receptor Antagonists        -   1. GT-2331            (3-((1R,2R)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl)-1H-imidazole,            also known as PERCEPTIN);        -   2. Ciproxifan (Cyclopropyl-(4-(3-1H-imidazol-4-yl)            propyloxy)phenyl)methanone, also known as BP 2359 or            Compound 359);        -   3. Compound 421 (imidazoylpropanol derivative, INSERM            (France)/Bioprojet);        -   4. FUB 181 (3-(4-chlorophenyl)propyl-3-(1H-imidazol-4-yl)            propyl ether);        -   5. GR 175737 (3-((4-chlorophenyl)methyl)-5-(2-(1H-imidazol            -4-yl)ethyl)-1,2-oxadiazole);        -   6. GT 2227 (4-(6-cyclohexyl-3(Z)-hexenyl)imidazole maleate);        -   7. GT 2394            ((1R,2R)-(trans-2-Imidazol-4-ylcyclopropyl)-(cyclohexylmethoxy)carboxamide);        -   8. GT-2016 (piperidine,            1-(5-cyclohexyl-1-oxopentyl)-4-(1H-imidazol-4-yl)-);        -   9. Imoproxifan            (1-(4-(3-(1H-imidazol-4-yl)propoxy)phenyl)ethan -1-one            oxime);        -   10.1 Impentamine (by Berlin Free University);        -   11.Abbott Laboratories H3 antagonist for Attention deficit            Hyperactivity Disorder (ADHD);        -   12.Gliatech (USA) H3 antagonist for eating disorder;        -   13.Series of novel carbamates as derivatives of            3-(1H-imidazol-4-yl)propanol with an N-alkyl chain;        -   14.Series of analogs with a neutral linker leading to            4-(1H-imidazol-4-ylmethyl)benzene;        -   15.Urea,            N-4-(1H-imidazol-4-ylmethyl)phenylmethyl-N′-(3,5-dichlorophenyl)-,            monohydrochloride;        -   16.Sch-50971 (1H-imidazole,            4-[(3R,4R)-4-methyl-3-pyrrolidinyl]-);        -   17.Thioperamide            (N-cyclohexyl-4-(1H-imidazol-4-yl)-1-piperidinecarbothioamide,            also known as MR 12842);        -   18. UCL-1283 (by University College London);        -   19. UCL-1390 (4-(3-(1H-imidazol-4-yl)propoxy)benzonitrile);        -   20. UCL-1409 ((phenoxyalkyl)imidazoles);        -   21.UCL-1972 (by University College London);        -   22.Verongamine (benzenepropanamide,            3-bromo-.alpha.-(hydroxyimino)-N-[2-(1H-imidazol-4-yl)ethyl]-4-methoxy-,(E)-);        -   23.VUF-9153 (Carbamimidothioic acid,            [(4-chlorophenyl)methyl]-, 3-(1H-imidazol-4-yl)propyl ester,            also known as Clobenpropit);    -   (H) Pancreatic Lipase Inhibitors        -   1. Orlistat (L-Leucine, N-formyl-,            1-((3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl ester,            (2S-(2alpha(R*),3beta))-, or N formyl-L-leucine            (2S-(2alpha(R*),3beta))-1-((3-hexyl-4oxo-2-oxetanyl)methyl)dodecyl            ester, also known as Orlipastat, RO 180647,            Tetrahydrolipstatin (THL), XENICAL, or ZENICAL);        -   2. ATL 962 (also known as AZM 119 or Alizyme);        -   3. GelTex (Anti-obesity therapeutics);        -   4. AZM-131 (by Yakurigaku Chuo Kenkyusho/Institute of Food            Research);        -   5. RED 103004 (XiMed Group (United Kingdom)/BioClin);    -   (I) Alpha Melanocyte Stimulating Hormone Analogues        -   1. Melanotan II            (acetyl-norleucyl-aspartyl-histidyl-D-phenylalanyl-arginyl-tryptophyl-lysinamide            C-4,2-N-6.7-lactam, also known as MT II);        -   2. MBU-23, MBU-23, MBU-24, MBU-27, MBU-28 and MBU-29 (all            described in WO 009827113);        -   3. MSH fusion toxin (also known as DAB389MSH, antimelanoma,            chimaera);        -   4. SHU-9119 (L-Lysinamide,            N-acetyl-L-norleucyl-L-.alpha.-aspartyl-L-histidyl-3-(2-naphthalenyl)-D-alanyl-L-arginyl-L-tryptophyl-,            (2.fwdarw.7)-lactam, also known as MBX 36);        -   5. SHU-9005 (a substituted derivative of alpha-MSH);        -   6. ZYC-200 (alpha-MSH, Schepens/ZYCOS with BIOTOPE            expression cassette system);    -   (J) Mixed Serotonin Reuptake Inhibitor with Serotonin or Alpha        Adrenergic Antagonist Activity        -   1. Nefazodone            (2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one,            also known as MJ 13754, MS 13754, BMY 13754, BMY 137541,            SERZONE, DUTONIN, RESERIL, NEFADAR, NIFEREL, MENFAZONA,            RULIVAN, DEPREFAX, or SERZONIL);        -   2. YM 992 ((S)-2-(((7-fluoro-2,3-dihydro-1H-inden-4-yl)            oxy)methyl)morpholine hydrochloride, or            (S)-2-(((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)methyl)morpholine            hydrochloride, also known as YM 35992);        -   3. A 80426 ((R)—N-methyl-N-((1,2,3,4-tetrahydro-5-methoxy            -1-naphthalenyl)methyl)-6-benzofuranethanamine);        -   4. 5-HT1A antagonist (by Vita-Invest, Spain);    -   5. Nefazodone metabolite (by Sepracor, USA);        -   6. Serotonin reuptake inhibitors/serotonin 1A antagonists            (Wyeth-Ayerst);    -   (K) Appetite-Suppressants Acting Through Adrenergic Mechanisms        -   1. benzphetamine;        -   2. phenmetrazine;        -   3. phentermine;        -   4. diethylpropion;        -   5. mazindol;        -   6. sibutramine;        -   7. phenylpropanolamine;        -   8. ephedrine;    -   (L) Mixed Serotonin & Dopamine Reuptake Inhibitors        -   1. BL-1834            (1-propanamine,3-dibenz(b,e)oxepin-11(6H)-ylidene-N,N-dimethyl);        -   2. NS-2389 or NS-2347 (GW-650250A, GW 650250);        -   3. (R)-Sibutramine;        -   4. NS-2359 (by NeuroSearch, Denmark);        -   5. RTI-112 or RTI-113 or RTI-177            (8-Azabicyclo(3.2.1)octane-2-carboxylic            acid,3-(4-chloro-3-methylphenyl)-8-methyl-, methyl ester,            hydrochloride, (1R,2S,3S,5S));        -   6. BSF-74681(Abbott);        -   7. Hyperforin trimethoxybenzoate (IDN-5491);    -   (M) Mixed Serotonin Reuptake Inhibitors and Dopamine Antagonist        -   1. SLV-310 (Solvay, Belgium);        -   2. EMD 86006            (3-(2-(3-(4-fluorophenyl)benzylamino)ethoxy)benzonitrile);        -   3. SLV 301 (by Solvay);    -   (N) Norepinephrine & Serotonin Reuptake Inhibitors (NSRI)        -   1. Milnacipran (Cyclopropanecarboxamide, 2-(aminomethyl)-N,N            -diethyl-1-phenyl-, cis-(+/−)-, or            (±)-cis-2-(Aminomethyl)-N-diethyl-1-phenyl cyclopropane            carboxamide hydrochloride, also known as F-2207, F-2641,            TN-912, DALCIPRAN, IXEL, MIDACIPRAN, MIDALCIPRAN,            MILNACIPRAN SR, TOLEDOMIN);        -   2. Tramadol, Purdue (cyclohexanol,            2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/−),            also known as TRAMADOL, Tramadol, CR, or Toray);        -   3. Milnacipran (drug delivery system, sustained release);        -   4. Duloxetine            ((S)—N-methyl-gamma-(1-naphthalenyloxy)-2-thiophenepropanamine,            or            (+)-(S)—N-Methyl-gamma-(1-naphthyloxy)-2-thiophene-propylamine            hydrochloride, also known as LY 248686, duloxetine oxalate,            LY-223332, LY-223743, LY-223994, LY-227750, LY-227942,            LY-228993, LY-248686, LY-264452, LY-264453, LY-267826;        -   5. Naltrexone+tramadol            (morphinan-6-one,17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-,            (5alpha)-, mixt with cyclohexanol,            2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/−)-,            also known as PTI-601, tramadol+naltrexone, Pain T);        -   6. (S) sibutramine            ((S)-1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)cyclobutanemethanamine);        -   7. Tramadol, Labopharm (cyclohexanol, 2-((dimethylamino)            methyl)-1-(3-methoxyphenyl)-, cis-(+/−), also known as            tramadol, Contramid);        -   8. F 98214TA (by FAES, Spain);        -   9. S 33005            ((−)-1-(1-Dimethylaminomethyl-5-methoxybenzocyclobutan-1-yl)cyclopentanol);        -   10.Tacrine analogues, SIDR;    -   (O) Serotonin, Norepinephrine and Dopamine Reuptake Inhibitors        -   1. Sibutramine (cyclobutanemethanamine,1-(4-chlorophenyl)-N,            N-dimethyl-alpha-(2-methylpropyl)-, or 1-(4-chlorophenyl)            -N,N-dimethyl-alpha-(2-methylpropyl)cyclobutanemetha namine            hydrochloride monohydrate, also known as Sibutramine            hydrochloride monohydrate, BTS-54354, BTS-54505, BTS-54524,            KES-524, MERIDIA, REDUCTIL, RADUCTIL, REDUCTASE, PLENTY,            ECTIVA);        -   2. Venlafaxine (cyclohexanol,            1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl], also known            as WY 45030, WY 45651, WY 45655, DOBUPAL, EFECTIN, EFEXOR,            EFFEXOR, ELAFAX, VANDRAL, TREVILOR);        -   3. Venlafaxine XR (cyclohexanol,            1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)-,            hydrochloride, also known as EFFEXOR XR,I EFFEXOR ER,            EFFEXOR XL, EFFEXOR LP, DOBUPAL RETARD, VANDRAL RETARD,            EFFEXOR-EXEL 75, EFEXOR XR, EFEXOR DEPOT, ELAFAX XR);        -   4. Venlafaxine (drug delivery system, OROS oral controlled            release, also known as venlafaxine, OROS, or EFEXOR XR);        -   5. (+)-Desmethylsibutramine (also known as DDMS,            Didesmethylsibutramine-Sepracor);        -   6. BTS-74398            (1-[1-(3,4-Dichlorophenyl)cyclobutyl]-2-(3-dimethylaminopropylthio)ethanone,            Abbott Pharmaprojects No. 6247);        -   7. Desmethylvenlafaxine (by Sepracor);    -   (P) Appetite-Suppressant Agents Acting Through Dopamine        Mechanisms        -   1. Apomorphine;    -   (Q) Selective Norepinephrine (Noradrenaline) Reuptake Inhibitors        -   1. Reboxetine            ((2S)-rel-2-((R)-(2-ethoxyphenoxy)phenylmethyl) morpholine,            or morpholine, 2-[(2-ethoxyphenoxy)phenylmethyl]-, (R,S)—,            methanesulfonate, also known as reboxetine mesylate (USAN),            FCE 20124, FCE 21684, PNU 155950E, EDRONAX, PROLIFT, VESTRA,            IRENON, NOREBOX);        -   2. Tomoxetine            ((gamma.R)—N-methyl-gamma-(2-methylphenoxy)benzenepropanamine,            or (−)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine            hydrochloride, also known as LY 139603, LY 135252, LY            139602);        -   3. Hydroxynortriptyline            ((E)-10-11-dihydro-5-(3-(methylamino))-5H-dibenzo-(a,d)            cyclohepten-10-ol);        -   4. LY 368975            ((R)—N-Methyl-3-[2-(methylsulfanyl)phenoxy]-3-phenyl-propylamine            hydrochloroide);    -   (R) Combined Norepinephrine and Dopamine Reuptake Inhibitors        -   1. Bupropion            (1-(3-chlorophenyl)-2-((1,1-dimethylethyl)amino)            -1-propanone, also known as bupropion hydrochloride (USAN),            bupropin, amfebutamone, BW 323U, WELLBUTRIN, QUOMEM, or            ZYBAN);        -   2. GW 320659            ((2S-(2alpha,3alpha,5alpha))-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol            hydrochloride, also known as 1555, 1555U88, BW 1555U88);        -   3. Hydroxy bupropion (also known as bupropion, R—, or            R-bupropion);        -   4. (−)Didesmethylsibutramine (also known as            (S)-didesmethylsibutramine, desmethylsibutramine, (−)-DDMS            or MERIDIA (urogenital));    -   (S) Mixed Norepinephrine Reuptake Inhibitor and Other        Neurotransmitter Antagonists        -   1. Zotepine (2-((8-chlorodibenzo            (b,f)thiepin-10-yl)oxy)-N,N-dimethylethylamine, also known            as LODOPIN, NIPOLEPT, ZOLEPTIL, ZOPITE, SETOUS, MAJORPIN);        -   2. MC1-225 (4-(2-fluorophenyl)-2-methyl-6-(piperazin-1-yl)            -3a,7a-dihydrothieno(2,3-d) pyrimidine, or            4-(2-Fluorophenyl)-6-methyl-2-piperazinothieno[2,3-d]pyrimidine            hydrochloride hydrate);        -   3. A 75200            ((R*,R*)-(+,−)-3-phenyl-1-((6,7,8,9-tetrahydronaphtho(1,2-d)-1,3-dioxol-6-yl)methyl)pyrrolidine);    -   (T) Combined Serotonin Reuptake Inhibitors and Sigma Receptor        Antagonists        -   1. E-5296 (by Esteve, Spain);        -   2. E-6276 (by Esteve, Spain);        -   3. E-5842 (pyridine,            4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(4-(1H-1,2,4-triazol-1-yl)butyl)-,            2-hydroxy-1,2,3-propanetricarboxylate (1:1));        -   4. E 5826 (citrate salt of E-5842);    -   (U) Other Neurotransmitter Modulators with Serotonin or        Norepinephrine Uptake Inhibitor Activity        -   1. Pirlindole (1H-pyrazino (3,2,1-jk) carbazole,            2,3,3a,4,5,6-hexahydro-8-methyl-, also known as CAS-125,            Pyrazidol, pirazidol, LIFRIL, IMPLEMENTOR);        -   2. NS-2330 (by NeuroSearch, Denmark);        -   3. VAN-H36 (by Vita-Invest, Spain);        -   4. UR 1827            (2-(1-Benzylpiperidin-4-yl)-1-[4-(5-methylpyrimidin-4-ylamino)phenyl]-1-ethanone);    -   (V) C-75 (Fatty Acid Synthase Inhibitor)    -   (W) S 15261 (L-4-(2-(2-(9-Fluorenyl)acetamido)ethyl)benzoic acid        2-(2-methoxy-2-(3-(trifluoromethyl)phenyl)ethylamino) ethyl        ester)    -   (X) S 100B (Neurotrophic Factor)    -   (Y) Stimulators of Uncoupling Protein Function    -   (Z) Cholecystokinin Agonists    -   (AA) androgens        -   1. dehydroepiandrosterone;        -   2. dehydroepiandrosterone derivatives (such as            etiocholandione);    -   (BB) Testosterone    -   (CC) Anabolic Steroids (eg, Oxandrolone)    -   (DD) Steroidal Hormones    -   (EE) Amylase Inhibitors    -   (FF) Enterostatin Agonists/Mimetics    -   (GG) Orexin/Hypocretin Antagonists    -   (HH) Urocortin Antagonists    -   (II) Bombesin Agonists    -   (JJ) Modulators of Protein Kinase A    -   (KK) Corticotropin-Releasing Factor Mimetics    -   (LL) Cocaine- and Amphetamine-Regulated Transcript Mimetics    -   (MM) Calcitonin-Gene Related Peptide Mimetics    -   (NN) Nizatidine (Axid)

Examples of lipid lowering agents include bile acid sequestrants, fibricacid derivatives, nicotinic acid, and HMGCoA reductase inhibitors.Specific examples include statins such as LIPITOR®, ZOCOR®, PRAVACHOL®,LESCOL®, CRESTOR®, and MEVACOR®, and pitavastatin (nisvastatin) (Nissan,Kowa Kogyo, Sankyo, Novartis) and extended release forms thereof, suchas ADX-159 (extended release lovastatin), as well as Colestid,Locholest, Questran, Atromid, Lopid, and Tricor.

Examples of blood pressure lowering agents include anti-hypertensiveagents, such as angiotensin-converting enzyme (ACE) inhibitors(Accupril, Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil,Univasc, Vasotec, and Zestril), adrenergic blockers (such as Cardura,Dibenzyline, Hylorel, Hytrin, Minipress, and Minizide) alpha/betaadrenergic blockers (such as Coreg, Normodyne, and Trandate), calciumchannel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS,Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia,Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensinII receptor antagonists (such as Atacand, Avapro, Cozaar, and Diovan),beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc,Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin,Toprol-XL, and Zebeta), vasodilators (such as Deponit, Dilatrate, SR,Imdur, Ismo, Isordil, Isordil Titradose, Monoket, Nitro-Bid, Nitro-Dur,Nitrolingual Spray, Nitrostat, and Sorbitrate), and combinations thereof(such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide,Uniretic, Vaseretic, Zestoretic).

F) Biological Example TR-FRET Assay

Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)experiments were performed to examine the functional response of ERR1(also known as ERR-α or ERR-1) ligands. The TR-FRET assay describedherein relied on the conformation of ERR1 for binding to a co-activatorpeptide: when a test compound binds to ERR1 and alters its conformation,it can disrupt the binding of the co-activator peptide. The componentsof this homogeneous secondary assay included: the ⁶His-tagged-ERR1LBD, aGST-labeled-hSRC2 co-activator polypeptide and a fluorescentdonor/acceptor pair from CIS bio international htrf/bioassays (Bedford,Mass.) using both an α-GST Europium Cryptate (Eu) label and anα⁶His-XL665 (allophycocyanin) fluorophore.

For TR-FRET measurements, the reaction was buffered in 25 mM Tris pH 8,2.5 mM Hepes, 20 mM KCl, 1 mM DTT, and 0.05 mg/mL BSA (-lipids). Thefinal concentrations of reagents were 6 nM of ERR1LBD, 6 nM GST-SRC-2peptide, 30 nM Eu cryptate, and 7.5 nM XL665. Reactions were allowed toreach equilibrium at 25° C. for 4-18 hours before collecting data on theAnalyst from LJL Biosystems (Molecular Devices Sunnyvale, Calif.). As atime-resolved method, the samples were excited at 340 nM and emissionwas collected for 1 ms at both 615 and 665 nm with delays of 400 and 75μs, respectively. Dose response curves were fitted using a hyperbolicequation and the data reported is the average of 3 independentexperiments.

Compounds listed in Tables II below were tested in the above assay, andthey are all active modulators of ERR1.

TABLE II TR-FRET data COMPOUND # EC₅₀ TR-FRET (μM) 1 0.0770 2 0.0120 30.0064 4 0.0231 5 0.0032 6 0.0045 7 0.0044 8 0.0730 9 0.0089 10 0.004911 0.0030 12 0.0150 13 0.0053 14 0.0065 15 0.0039 16 0.0025 17 0.0076 180.0018 19 0.0110 20 0.0194 21 0.0046 22 0.0140 23 0.0170 24 0.0120 250.0420 26 0.0360 27 0.0110 28 0.0060 29 0.0390 30 0.0110 31 0.0370 320.0086 33 0.2595 34 0.0308 35 0.0112 36 0.0048 37 0.0180 38 0.0568 390.0066 40 N/A 41 0.0077 42 0.0100 43 0.0190 44 0.0150 45 0.0097 460.0220 47 0.037 48 0.005

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of Formula (I)

wherein X is CH or N; R₁ is C₁₋₄alkyl, halo, or —C(O)—C₁₋₄alkyl; whereinsaid C₁₋₄alkyl may be substituted with halo; R₂ is halo, cyano, H,C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkoxy, —C(O)N(R⁵)(R⁶), or hydroxyl; whereinsaid C₁₋₄alkyl may be substituted with halo; R₃ is H, halo, —CN, orC₁₋₄alkyl; and R₄ is heteroaryl, C₁₋₄alkyl, cycloalkyl, or heterocyclyl;wherein said C₁₋₄alkyl may be substituted with one to five groups, saidgroups independently selected from halo, —OR⁵, cycloalkyl, —N(R⁵)(R⁶),—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —SO₂N(R⁵)(R⁶), —O—C₁₋₄alkyl—OR⁵, heterocyclyloptionally substituted with halo, oxo or C₁₋₄alkyl, and heteroaryloptionally substituted with C₁₋₄alkyl; wherein said cycloalkyl may besubstituted with one to three groups, said groups independently selectedfrom halo, —C(O)OR⁵, and C₁₋₄alkyl; wherein said heterocyclyl may beindependently substituted with one to three groups, said groupsindependently selected from halo, C₁₋₄alkyl, and —OR⁵; wherein saidC₁₋₄alkyl may be substituted with —OR⁵; wherein R⁵ and R⁶ areindependently H or C₁₋₄ alkyl; or an optical isomer, enantiomer,diastereomer, cis-trans isomer, racemate, or pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1 wherein X is CH; R₁ is—C(O)—C₁₋₂alkyl, —Cl, —Br, —I, or C₁₋₃alkyl; wherein said C₁₋₃alkyl maybe substituted with halo; R₂ is —CF₃, —F, —Cl, —Br, C₁₋₂alkoxy orhydroxyl; R₃ is H or halo; and R₄ is selected from


3. The compound of claim 2 wherein X is CH; R₁ is —CF₃, —Cl, —Br, or —I;R₂ is —CF₃, —OCH₃, —F or —Cl; and R₃ is H or halo.
 4. The compound ofclaim 2 wherein X is —CH; R₁ is —CF₃; R₂ is —CF₃, —OCH₃, or —Cl; and R₃is H.
 5. The compound of claim 1 wherein X is CH; R₁ is —C(O)—C₁₋₂alkyl,—Cl, —Br, —I, or C₁₋₃alkyl; wherein said C₁₋₃alkyl may be substitutedwith halo; R₂ is —CF₃, —F, —Cl, —Br, C₁₋₂alkoxy or hydroxyl; R₃ is H orhalo; and R₄ is selected from


6. The compound of claim 5 wherein X is CH; R₁ is —CF₃, —Cl, —Br, or —I;R₂ is —CF₃, —OCH₃, —F or —Cl; and R₃ is H or halo.
 7. The compound ofclaim 5 wherein X is —CH; R₁ is —CF₃; R₂ is —CF₃, —OCH₃, or —Cl; and R₃is H.
 8. The compound of claim 1 selected from1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid;4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)piperazin-2-one;5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-2-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-1,3-thiazol-4(5H)-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1-methyl-piperidin-4-ylamino)-thiazol-4-one;2-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one;(S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid; and4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid.
 9. The compound of claim 1 selected from4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid;(S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid; and4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid.
 10. The compound of claim 1 selected from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid;(S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid; and4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid.
 11. A pharmaceutical composition comprising at least one compoundof claim 1 and at least one pharmaceutically acceptable carrier.
 12. Apharmaceutical composition of claim 11, further comprising at least oneadditional agent, drug, medicament, antibody and/or inhibitor fortreating, ameliorating or inhibiting the progression of an ERR-αmediated disease.
 13. The pharmaceutical composition of claim 11comprising at least one compound selected from1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid;4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one;5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-2-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-1,3-thiazol-4(5H)-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1-methyl-piperidin-4-ylamino)-thiazol-4-one;2-(1-Aza-bicyclo[2.2.2]oct-3(R)-ylamino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)ethylamino]-thiazol-4-one;(S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid; and4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid.
 14. The pharmaceutical composition of claim 11 comprising at leastone compound selected from4-(2-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-piperazin-2-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(pyrrolidin-3S-ylamino)-thiazol-4-one;4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid;(S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid; and4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid.
 15. The pharmaceutical composition of claim 11 comprising at leastone compound selected from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid;(S,S)-4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclohexanecarboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-cyclopropanecarboxylicacid; and4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-butyricacid.
 16. A method of treating a subject suffering from or diagnosedwith a disease, disorder, or condition mediated by ERR-α activity,comprising administering to the subject a therapeutically effectiveamount of at least one compound of claim
 1. 17. A method according toclaim 16, wherein the disease, disorder, or condition is selected fromthe group consisting of bone-related disease, bone formation, cartilageformation, cartilage loss, cartilage degeneration, cartilage injury,ankylosing spondylitis, chronic back injury, gout, osteoporosis,osteolytic bone metastasis, multiple myeloma, chondrosarcoma,chondrodysplasia, osteogenesis imperfecta, osteomalacia, Paget'sdisease, polymyalgia rheumatica, pseudogout, arthritis, rheumatoidarthritis, infectious arthritis, osteoarthritis, psoriatic arthritis,reactive arthritis, childhood arthritis, Reiter's syndrome, andrepetitive stress injury.
 18. A method according to claim 16, whereinthe disease, disorder, or condition is selected from the groupconsisting of periodontal disease, chronic inflammatory airway disease,chronic bronchitis, and chronic obstructive pulmonary disease.
 19. Amethod according to claim 16, wherein the disease, disorder, orcondition is breast cancer.
 20. A method according to claim 16, whereinthe disease, disorder, or condition is selected from the groupconsisting of metabolic syndrome, obesity, disorders of energyhomeostasis, diabetes, lipid disorders, cardiovascular disorders,artherosclerosis, hyperglycemia, elevated blood glucose level, andinsulin resistance.
 21. The method of claim 16 comprising administeringto the subject a therapeutically effective amount of (a) at least onecompound of claim 1; and (b) at least one additional agent selected froman anti-diabetic agent, an anti-obesity agent, a lipid lowering agent,an anti-thrombotic agent, direct thrombin inhibitor, and a bloodpressure lowering agent, said administration being in any order.
 22. Themethod of claim 21 wherein the additional agent in (b) is ananti-obesity agent selected from CB1 antagonists, monoamine reuptakeinhibitors, MTP inhibitors and lipase inhibitors.
 23. The method ofclaim 21 wherein the additional agent in (b) is an anti-diabetic agentselected from metformin, DPP-IV inhibitors, GLP-1 mimetics, glucokinasemodulators, glucagon antagonists, SGLT2 inhibitors, PPARγ agonists andGPR119 modulators.
 24. The method of claim 21 wherein the additionalagent in (b) is selected from Metformin, Sitagliptin and Pioglitazone.25. A method for inhibiting the progression of an ERR-α-mediatedcondition in a subject in need thereof, comprising administering to saidsubject a therapeutically effective amount of at least one compoundaccording to claim
 1. 26. A method for treating a prediabetic conditionin a subject in need thereof, comprising administering to said subject atherapeutically effective amount of at least one compound according toclaim
 1. 27. The method of claim 16 wherein the therapeuticallyeffective amount of the compound of claim 1 is from about 0.1 mg/dose toabout 5000 mg/dose.
 28. The method of claim 27 wherein thetherapeutically effective amount of the compound of claim 1 is fromabout 0.5 mg/dose to about 1000 mg/dose.
 29. The method of claim 27wherein the therapeutically effective amount of the compound of claim 1is from about 1 mg/dose to about 100 mg/dose.
 30. A process for making apharmaceutical composition comprising admixing any of the compoundsaccording to claim 1 and a pharmaceutically acceptable carrier.